Antagonists of the trpv1 receptor and uses thereof

ABSTRACT

The present application is directed to compounds that are TRPV1 antagonictc and have formula (I) 
     
       
         
         
             
             
         
       
     
     wherein variables Ar 1 , L 1 , R 1 , R 2 , R 3 , R 4 , R 5 , Y 1 , Y 2 , and Y 3 , are as defined in the description, which are useful for treating disorders caused by or exacerbated by vanilloid receptor activity.

RELATED APPLICATION

This application claims priority to U.S. Patent Application Ser. No.60/875,890, filed Dec. 20, 2006 and is incorporated herein by referencein its entirety.

FIELD AND BACKGROUND

The present application relates to compounds of formula (I), which areuseful for treating disorders caused by or exacerbated by vanilloidreceptor activity. The present application also includes pharmaceuticalcompositions containing compounds of formula (I) and methods fortreating pain, bladder overactivity, and urinary incontinence using saidcompounds and said pharmaceutical compositions.

Nociceptors are primary sensory afferent (C and Aδ fibers) neurons thatare activated by a wide variety of noxious stimuli including chemical,mechanical, thermal, and proton (pH<6) modalities. The lipophillicvanilloid, capsaicin, activates primary sensory fibers via a specificcell surface capsaicin receptor, cloned as the transient receptorpotential vanilloid-1 (TRPV1). The intradermal administration ofcapsaicin is characterized by an initial burning or hot sensationfollowed by a prolonged period of analgesia. The analgesic component ofTRPV1 receptor activation is thought to be mediated by acapsaicin-induced desensitization of the primary sensory afferentterminal. Thus, the long lasting anti-nociceptive effects of capsaicinhas prompted the clinical use of capsaicin analogs as analgesic agents.Further, capsazepine, a capsaicin receptor antagonist can reduceinflammation-induced hyperalgesia in animal models. TRPV1 receptors arealso localized on sensory afferents, which innervate the bladder.Capsaicin or resiniferatoxin has been shown to ameliorate incontinencesymptoms upon injection into the bladder.

The TRPV1 receptor has been called a “polymodal detector” of noxiousstimuli since it can be activated in several ways. The receptor channelis activated by capsaicin and other vanilloids and thus is classified asa ligand-gated ion channel. TRPV1 receptor activation by capsaicin canbe blocked by the competitive TRPV1 receptor antagonist, capsazepine.The channel can also be activated by protons. Under mildly acidicconditions (pH 6-7), the affinity of capsaicin for the receptor isincreased, whereas at pH<6, direct activation of the channel occurs. Inaddition, when membrane temperature reaches 43° C., the channel isopened. Thus heat can directly gate the channel in the absence ofligand. The capsaicin analog, capsazepine, which is a competitiveantagonist of capsaicin, blocks activation of the channel in response tocapsaicin, acid, or heat.

The channel is a nonspecific cation conductor. Both extracellular sodiumand calcium enter through the channel pore, resulting in cell membranedepolarization. This depolarization increases neuronal excitability,leading to action potential firing and transmission of a noxious nerveimpulse to the spinal cord. In addition, depolarization of theperipheral terminal can lead to release of inflammatory peptides suchas, but not limited to, substance P and CGRP, leading to enhancedperipheral sensitization of tissue.

Recently, two groups have reported the generation of a “knock-out” mouselacking the TRPV1 receptor. Electrophysiological studies of sensoryneurons (dorsal root ganglia) from these animals revealed a markedabsence of responses evoked by noxious stimuli including capsaicin,heat, and reduced pH. These animals did not display any overt signs ofbehavioral impairment and showed no differences in responses to acutenon-noxious thermal and mechanical stimulation relative to wild-typemice. The TRPV1 (−/−) mice also did not show reduced sensitivity tonerve injury-induced mechanical or thermal nociception. However, theTRPV1 knock-out mice were insensitive to the noxious effects ofintradermal capsaicin, exposure to intense heat (50-55° C.), and failedto develop thermal hyperalgesia following the intradermal administrationof carrageenan.

The compounds of the present application are novel TRPV1 antagonists andhave utility in treating pain, inflammatory hyperalgesia,ostheoarthritic pain, chronic lower pain, migraine, bladderoveractivity, and urinary incontinence.

SUMMARY

The present application is directed to compounds of formula (I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

L₁ is a bond, alkylene, or cycloalkyl;

Y₁ is —N(R_(b))— or —C(R_(8a)R_(8b))—;

Y₂ is ═O, ═S or ═N—CN;

Y₃ is —N(R_(c))—;

Ar₁ is aryl or heteroaryl when L₁ is cycloalkyl; or Ar₁ is a monocyclicheterocycle fused to an aryl or a monocyclic heterocycle fused to amonocyclic heteroaryl when L₁ is a bond or alkylene;

wherein each Ar₁ is optionally substituted with 1, 2, 3, 4, or 5substituents as represented by R_(w), two R_(w) that are attached to thesame carbon atom of the monocyclic heterocycle, together with the carbonatom to which they are attached, optionally form a monocyclic cycloalkylring wherein said monocyclic cycloalkyl ring is optionally substitutedwith 1, 2, or 3 substituents selected from the group consisting of oxo,alkyl, and haloalkyl;

R₁ is hydrogen, hydroxy or alkoxy;

R_(w), R₂, R₃, R₄, and R₅, are each independently hydrogen, alkenyl,alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio,alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl,cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl,haloalkylthio, halogen, hydroxy, hydroxyalkyl, nitro, R_(e)OS(O)₂—,R_(f)R_(g)N—, (R_(f)R_(g)N)alkyl, (R_(j)R_(k)N)carbonyl,(R_(j)R_(k)N)carbonylalkyl or (R_(j)R_(k)N)sulfonyl;

R_(8a) is hydrogen or alkyl;

R_(8b) is hydrogen or alkyl; or

R_(8a) and R_(8b) taken together with the carbon atoms to which they areattached, form a 3-6 membered cycloalkyl ring;

R_(b) and R_(c) are each independently hydrogen or alkyl;

R_(e) is alkyl, haloalkyl, aryl, or arylalkyl;

R_(f) and R_(g), at each occurrence, are each independently hydrogen,alkenyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, arylalkyl, arylcarbonyl,carboxyalkyl, cycloalkylalkyl, haloalkyl, heteroarylalkyl, orheteroarylcarbonyl; or

R_(f) and R_(g) taken together with the nitrogen atom to which they areattached form a heterocyclic ring; and

R_(j) and R_(k), at each occurrence, are each independently hydrogen,alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl,carboxyalkyl, cycloalkylalkyl, haloalkyl, or hydroxyalkyl.

The inventions further relates to a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof, and one or more pharmaceutically acceptablecarriers, alone or in combination with one or more nonsteroidalanti-inflammatory drug (NSAID).

The application is also directed to a method for inhibiting the TRPV1receptor in mammals using compounds of formula (I).

The application also provides a method of treating disorders, whereinthe disorder is pain, especially, inflammatory hyperalgesia,ostheoarthritic pain, chronic lower pain, allodynia, migraine. Methodsof controlling pain and treating bladder overactivity and urinaryincontinence are also disclosed.

Yet further, the invention provides the use of a compound of formula(I), or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for the treatment of disease or disorders as definedherein below, alone or in combination with one or more nonsteroidalanti-inflammatory drug (NSAID).

It is to be understood that both the foregoing general description andthe following detailed description are exemplary, but are notrestrictive, of the invention.

DETAILED DESCRIPTION Compounds

Compounds of formula (I) are disclosed in this invention,

wherein Ar₁, L₁, R₁, R₂, R₃, R₄, R₅, Y₁, Y₂, and Y₃, are defined abovein the Summary of the Invention and below in the Detailed Description.Preferably, compounds of the invention are TRPV1 antagonists. Further,compositions comprising such compounds and methods for treatingconditions and disorders using such compounds and compositions are alsodisclosed.

In various embodiments, the present invention provides at least onevariable that occurs more than one time in any substituent or in thecompound of the invention or any other formulae herein. Definition of avariable on each occurrence is independent of its definition at anotheroccurrence. Further, combinations of substituents are permissible onlyif such combinations result in stable compounds. Stable compounds arecompounds, which can be isolated from a reaction mixture.

Compounds of the application can have the formula (I) as describedabove. More particularly, compounds of formula (I) can include, but arenot limited to compounds wherein Y₁ is —N(R_(b))— or —C(R_(8a)R_(8b))—,Y₃ is —N(R_(c))—, and Y₂ is either ═O, ═S or ═N—CN. Preferred compoundsare those in which Y₁ is —N(R_(b))—, Y₂ is O, and Y₃ is —N(R_(c))—. Thecompounds of the present application include compounds wherein Y₁ is—N(R_(b))—, Y₂ is O, and Y₃ is —N(R_(c))—, and L₁ is a 4-7 memberedcycloalkyl ring. More particularly, L₁ is cyclopentyl or cyclohexyl.Compounds of the present application include compounds wherein Y₁ is—N(R_(b))—, Y₂ is O, and Y₃ is —N(R_(c))—, L₁ is cyclopentyl orcyclohexyl, and Ar₁ is optionally substituted aryl, preferablyoptionally substituted phenyl. Compounds of the present invention alsoinclude those in which Y₁ is —N(R_(b))—, Y₂ is O, and Y₃ is —N(R_(c))—,and L₁ is a 4-7 membered cycloalkyl ring, and Ar₁ is optionallysubstituted heteroaryl. The present application includes compounds inwhich Y₁ is —N(R_(b))—, Y₂ is O, and Y₃ is —N(R_(c))— and L₁ is a bond.Compounds included in this group may include those in which Ar₁ is amonocyclic heterocycle fused to a phenyl, but also may include those inwhich Ar₁ is a monocyclic heterocycle fused to a bicyclic aryl.Preferred compounds are those in which Y₁ is —N(R_(b))—, Y₂ is O, and Y₃is —N(R_(c))—, L₁ is a bond, Ar₁ is 3,4-dihydro-2H-chromen-3-yl, R₁ ishydroxy; and R₂ is hydrogen. Other preferred compounds are those inwhich Y₁ is —N(R_(b))—, Y₂ is O, and Y₃ is —N(R_(c))—, L₁ is a bond, Ar₁is 3,4-dihydro-2H-chromen-4-yl, R₁ is hydroxy; and R₂ is hydrogen. Otherpreferred compounds include those wherein Y₁ is —N(R_(b))—, Y₂ is O, andY₃ is —N(R_(c))—, L₁ is a bond, Ar₁ is a monocyclic heterocycle fused toa bicyclic aryl, R₁ is hydroxy, and R₂ is hydrogen. For example,compounds of the invention include those wherein Y₁ is —N(R_(b))—, Y₂ isO, and Y₃ is —N(R_(c))—, L₁ is a bond, Ar₁ is3,4,7,8,9,10-hexahydro-2H-benzo[h]chromen-4-yl, R₁ is hydroxy, and R₂ ishydrogen. Among the compounds of the present application are those inwhich Y₁ is —N(R_(b))—, Y₂ is O, and Y₃ is —N(R_(c))—, L₁ is a bond, Ar₁is a monocyclic heterocycle fused to a phenyl, (for example, Ar₁ is1,2,3,4-tetrahydro-quinolin-4-yl), R₁ is hydroxy, and R₂ is hydrogen.Also included are compounds wherein Y₁ is —N(R_(b))—, Y₂ is O, and Y₃ is—N(R_(c))—, L₁ is a bond, Ar₁ is a monocyclic heterocycle fused to aphenyl, (for example, Ar₁ is 1,2,3,4-tetrahydro-quinolin-3-yl), R₁ ishydroxy, and R₂ is hydrogen. The compounds of the present applicationalso include compounds wherein Y₁ is —N(R_(b))—, Y₂ is O, and Y₃ is—N(R_(c))—, and L₁ is alkylene. Within this group of compound areincluded those in which Y₁ is —N(R_(b))—, Y₂ is O, and Y₃ is —N(R_(c))—,L₁ is alkylene (for example, L₁ is CH₂), Ar₁ is a monocyclic heterocyclefused to a phyenyl, (for example, Ar₁ is 3,4-dihydro-2H-chromen-2-yl,3,4-dihydro-2H-chromen-3-yl, or 3,4-dihydro-2H-chromen-4-yl), R₁ ishydroxy; and R₂ is hydrogen. Also included in the group are those inwhich Y₁ is —N(R_(b))—, Y₂ is O, and Y₃ is —N(R_(c))—, L₁ is alkylene(for example, L₁ is CH₂), and Ar₁ is 1,2,3,4-tetrahydro-quinolin-2-yl,1,2,3,4-tetrahydro-quinolin-3-yl, or 1,2,3,4-tetrahydro-quinolin-4-yl,R₁ is hydroxy; and R₂ is hydrogen. Other included compounds are those inwhich Y₁ is —N(R_(b))—, Y₂ is O, and Y₃ is —N(R_(c))—, L₁ is alkylenylor a bond, and Ar₁ is a monocyclic heteroaryl.

Specific embodiments contemplated as part of the application include,but are not limited to compounds of formula (I), or salts or prodrugsthereof, for example:

-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{(3R)-3-[4-(trifluoromethyl)phenyl]cyclohexyl}urea;-   N-{(3S)-3-[4-(dimethylamino)phenyl]cyclopentyl}-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-3,4-dihydro-2H-chromen-3-yl-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-(8-tert-butyl-3,4-dihydro-2H-chromen-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(7-methoxy-3,4-dihydro-2H-chromen-3-yl)urea;-   N-(6-chloro-3,4-dihydro-2H-chromen-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-(8-tert-butyl-3,4-dihydro-2H-chromen-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-3,4,7,8,9,10-hexahydro-2H-benzo[h]chromen-4-yl-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(6-methyl-3,4-dihydro-2H-chromen-4-yl)urea;-   N-[(4R)-3,4-dihydro-2H-chromen-4-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-(3,4-dihydro-2H-chromen-2-ylmethyl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-[(7-ethoxy-3,4-dihydro-2H-chromen-2-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[(6-methyl-3,4-dihydro-2H-chromen-2-yl)methyl]urea;-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[(8-isopropyl-3,4-dihydro-2H-chromen-2-yl)methyl]urea;-   N-(8-tert-butyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-(1-benzyl-1,2,3,4-tetrahydroquinolin-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-[1-benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)urea;-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]urea;-   N-(1-benzyl-1,2,3,4-tetrahydroquinolin-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-[1-benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)urea;-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]urea;-   N-[(1-benzyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-{[1-benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl]methyl}-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl]methyl}urea;-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{(3R)-3-[4-(trifluoromethyl)phenyl]cyclohexyl}urea;    and-   N-{(3S)-3-[4-(dimethylamino)phenyl]cyclopentyl}-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea.

DEFINITION OF TERMS

All patents, patent applications, and literature references cited in thespecification are herein incorporated by reference in their entirety. Inthe case of inconsistencies, the present disclosure, includingdefinitions, will prevail.

As used throughout this specification and the appended claims, thefollowing terms have the following meanings:

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through anotheralkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of alkoxyalkylinclude, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl,2-methoxyethyl, and methoxymethyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxycarbonylalkyl” as used herein, means an alkoxycarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkoxycarbonylalkyl include, but are not limited to,3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and2-tert-butoxycarbonylethyl.

The term “alkyl” as used herein, means a straight or branched chainsaturated hydrocarbon containing from 1 to 10 carbon atoms.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonylalkyl” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkylcarbonylalkyl include, but are not limited to, 2-oxopropyl,3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.

The term “alkylcarbonyloxy” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom. Representative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylthio” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited,methylthio, ethylthio, tert-butylthio, and hexylthio.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl,” as used herein, means phenyl, a bicyclic aryl or atricyclic aryl. The bicyclic aryl is naphthyl, or a phenyl fused to amonocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl.The bicyclic aryl of the present application are attached to the parentmolecular moiety through any available carbon atom contained within thebicyclic aryl group. Representative examples of the bicyclic arylinclude, but are not limited to, dihydroindenyl, indenyl, naphthyl,dihydronaphthalenyl, and 1,2,3,4-tetrahydronaphthalenyl. The tricyclicaryl is a bicyclic aryl fused to a monocyclic cycloalkyl, or a bicyclicaryl fused to a monocyclic cycloalkenyl, or a bicyclic aryl fused to aphenyl. The tricyclic aryl is attached to the parent molecular moietythrough any substitutable carbon atom contained within the tricyclicaryl. Representative examples of tricyclic aryls include, but are notlimited to, anthracene, phenanthrene, dihydroanthracenyl, fluorenyl, andtetrahydrophenanthrenyl.

The aryl groups of this application are optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonyloxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl,alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, arylalkyl,carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen,haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, mercapto, nitro, oxo,—NZ₁Z₂ and (NZ₃Z₄)carbonyl, unless stated otherwise; and wherein thearyl moiety of the arylalkyl is optionally substituted with 1, 2, 3, 4,or 5 substituents selected from the group consisting of alkyl,haloalkyl, alkoxy, haloalkoxy, and halogen.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of arylalkyl include,but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “arylcarbonyl,” as used herein, means a aryl group appended tothe parent molecular moiety through a carbonyl group, as defined herein.

The term “azido” as used herein, means a —N₃ group.

The term “carbonyl” as used herein, means a —C(O)— group.

The term “carboxy” as used herein, means a —CO₂H group.

The term “carboxyalkyl” as used herein, means a carboxy group, asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein. Representative examples ofcarboxyalkyl include, but are not limited to, carboxymethyl,2-carboxyethyl, and 3-carboxypropyl.

The term “cyano” as used herein, means a —CN group.

The term “cyanoalkyl” as used herein, means a cyano group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of cyanoalkyl include,but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

The term “cycloalkenyl” as used herein, means a monocyclic or bicyclicring system containing from 3 to 10 carbons and containing at least onecarbon-carbon double bond. Representative examples of monocyclic ringsystems include, but are not limited to, 2-cyclohexen-1-yl,3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl and 3-cyclopenten-1-yl.Bicyclic ring systems are exemplified by a monocyclic cycloalkenyl ringfused to a monocyclic cycloalkyl ring, or a monocyclic cycloalkenyl ringfused to a monocyclic cycloalkenyl ring. The bicyclic cycloalkenylgroups of the present application are appended to the parent molecularmoiety through any substitutable carbon atom within the group.Representative examples of bicyclic cycloalkenyls include, but are notlimited to 4,5-dihydro-benzo[1,2,5]oxadiazole,3a,4,5,6,7,7a-hexahydro-1H-indenyl, 1,2,3,4,5,6-hexahydro-pentalenyl and1,2,3,4,4a,5,6,8a-octahydro-pentalenyl.

The term “cycloalkyl” as used herein, means a monocyclic or bicycliccycloalkyls. Monocyclic cycloalkyls are exemplified by saturated cyclichydrocarbon groups containing from 3 to 8 carbon atoms in the rings.Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicycliccycloalkyl groups of the present application are exemplified by amonocyclic cycloalkyl fused to a monocyclic cycloalkyl. The bicycliccycloalkyl groups of the present application are appended to the parentmolecular moiety through any substitutable carbon atom within thegroups. Representative examples of bicyclic cycloalkyls include, but arenot limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, andbicyclo[4.2.1]nonane.

The cycloalkenyl and the cycloalkyl groups of the present applicationare optionally substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy,alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano,formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto,oxo, —NZ₁Z₂ or (NZ₃Z₄)carbonyl, unless stated otherwise.

The term “cycloalkylalkyl,” as used herein, means a cycloalkyl groupappended to the parent molecular moiety through an alkylene group, asdefined herein.

The term “formyl” as used herein, means a —C(O)H group.

The term “formylalkyl” as used herein, means a formyl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy” as used herein, means an alkoxy group, as definedherein, in which one, two, three, four, five or six hydrogen atoms arereplaced by halogen. Representative examples of haloalkoxy include, butare not limited to, trifluoromethoxy, difluoromethoxy,2,2,2-trifluoroethoxy, and 2,2-difluoroethoxy.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein. Representative examples of haloalkylinclude, but are not limited to, chloromethyl, 2-fluoroethyl,trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “haloalkylthio” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through a sulfuratom.

The term “heteroaryl,” as used herein, means a monocyclic heteroaryl ora bicyclic heteroaryl. The monocyclic heteroaryl is a 5 or 6 memberedring containing at least one heteroatom independently selected from thegroup consisting of O, N, and S. The 5 membered ring contains two doublebonds and may contain one, two, three or four heteroatoms. The 6membered ring contains three double bonds and may contain one, two,three or four heteroatoms. The 5 or 6 membered heteroaryl is connectedto the parent molecular moiety through any carbon atom or any nitrogenatom contained within the heteroaryl. Representative examples ofmonocyclic heteroaryl include, but are not limited to, furyl,imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclicheteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or amonocyclic heteroaryl fused to a monocyclic cycloalkyl, or monocyclicheteroaryl fused to a monocyclic cycloalkenyl, or monocyclic heteroarylfused to a monocyclic heteroaryl, or monocyclic heteroaryl fused to amonocyclic heterocycle. The bicyclic heteroaryl groups of the presentapplication are appended to the parent molecular moiety through anysubstitutable carbon atom within the groups. —Representative examples ofbicyclic heteroaryls include, but are not limited to, benzofuranyl,benzoxadiazolyl, 1,3-benzothiazolyl, benzimidazolyl, benzodioxolyl,benzothiophenyl, chromenyl, cinnolinyl, furopyridine, indolyl,indazolyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine,quinolinyl, thienopyridine and thienopyridinyl.

The heteroaryl groups of the present application are optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio,alkylthioalkyl, alkynyl, arylalkyl, carboxy, carboxyalkyl, cyano,cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,hydroxyalkyl, mercapto, nitro, oxo, —NZ₁Z₂ or (NZ₃Z₄)carbonyl, unlessstated otherwise, and wherein the aryl moiety of the arylalkyl isoptionally substituted with 1, 2, 3, 4, or 5 substituents selected fromthe group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, andhalogen; unless otherwise stated. Heteroaryl groups of the presentapplication that are substituted with hydroxyl groups may be present astautomers. The heteroaryl rings of the present application encompasseall tautomers including non-aromatic tautomers.

The term “heteroarylalkyl,” as used herein, means a heteroaryl groupappended to the parent molecular moiety through an alkylene group, asdefined herein.

The term “heteroarylcarbonyl,” as used herein, means a heteroaryl groupappended to the parent molecular moiety through a carbonyl group, asdefined herein.

The term “monocyclic heterocycle” or “monocyclic heterocyclic” as usedherein, is a 3, 4, 5, 6 or 7 membered ring containing at least oneheteroatom independently selected from the group consisting of O, N andS. The 3 or 4 membered ring contains 1 heteroatom selected from thegroup consisting of O, N and S. The 5 membered ring contains zero or onedouble bond and one or two heteroatoms selected from the groupconsisting of O, N and S. The 6 or 7 membered ring contains zero, one ortwo double bonds and one or two heteroatoms selected from the groupconsisting of O, N and S. The monocyclic heterocycle is connected to theparent molecular moiety through any substitutable carbon atom within themonocyclic heterocycle. Representative examples of monocyclicheterocycle include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyran, tetrahydrothienyl,thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl,thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone),thiopyranyl, and trithianyl.

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, is appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “hydroxy-protecting group” or “O-protecting group” means asubstituent that protects hydroxyl groups against undesirable reactionsduring synthetic procedures. Examples of hydroxy-protecting groupsinclude, but are not limited to, substituted methyl ethers, for example,methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,2-(trimethylsilyl)-ethoxymethyl, benzyl, and triphenylmethyl,tetrahydropyranyl ethers, substituted ethyl ethers, for example,2,2,2-trichloroethyl and t-butyl, silyl ethers, for example,trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, cyclicacetals and ketals, for example, methylene acetal, acetonide andbenzylidene acetal, cyclic ortho esters, for example, methoxymethylene,cyclic carbonates, and cyclic boronates. Commonly usedhydroxy-protecting groups are disclosed in T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley &Sons, New York (1999).

The term “mercapto” as used herein, means a —SH group.

The term “nitrogen protecting group” as used herein, means those groupsintended to protect an amino group against undesirable reactions duringsynthetic procedures. Preferred nitrogen protecting groups are acetyl,benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl,tert-butoxycarbonyl (Boc), tert-butylacetyl, trifluoroacetyl, andtriphenylmethyl (trityl).

The term “nitro” as used herein, means a —NO₂ group.

The term “NZ₁Z₂” as used herein, means two groups, Z₁ and Z₂, which areappended to the parent molecular moiety through a nitrogen atom. Z₁ andZ₂ are each independently hydrogen, alkyl, alkoxyalkyl, alkylcarbonyl,or formyl. In certain instances within the present invention, Z₁ and Z₂taken together with the nitrogen atom to which they are attached form amonocyclic heterocycle wherein said monocyclic heterocycle is optionallysubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of alkyl, haloalkyl, and oxo. Representative examples ofNZ₁Z₂ include, but are not limited to, amino, methylamino, acetylamino,acetylmethylamino, phenylamino, benzylamino, azetidinyl, pyrrolidinyland piperidinyl.

The term “NZ₃Z₄” as used herein, means two groups, Z₃ and Z₄, which areappended to the parent molecular moiety through a nitrogen atom. Z₃ andZ₄ are each independently hydrogen, alkyl, or haloalkyl. Representativeexamples of NZ₃Z₄ include, but are not limited to, amino, methylamino,phenylamino and benzylamino.

The term “(NZ₃Z₄)carbonyl” as used herein, means a NZ₃Z₄ group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples of(NZ₃Z₄)carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “oxo” as used herein, means a ═O moiety.

The term “sulfinyl” as used herein, means a —S(O)— group.

The term “sulfonyl” as used herein, means a —SO₂— group.

The term “tautomer” as used herein means a proton shift from one atom ofa compound to another atom of the same compound wherein two or morestructurally distinct compounds are in equilibrium with each other.

Compounds of the present application may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The presentapplication contemplates various stereoisomers and mixtures thereof andthese are specifically included within the scope of this application.Stereoisomers include enantiomers and diastereomers, and mixtures ofenantiomers or diastereomers. Individual stereoisomers of compounds ofthe present application may be prepared synthetically from commerciallyavailable starting materials that contain asymmetric or chiral centersor by preparation of racemic mixtures followed by resolution which iswell known to those of ordinary skill in the art. These methods ofresolution are exemplified by (1) attachment of a mixture of enantiomersto a chiral auxiliary, separation of the resulting mixture ofdiastereomers by recrystallization or chromatography and liberation ofthe optically pure product from the auxiliary or (2) direct separationof the mixture of optical enantiomers on chiral chromatographic columns.

Compounds of the formula (I) contain at least 2 stereogenic centers. Twosterogenic centers contained within the compounds of the presentapplication are contained within L₁ which is defined as cycloalkyl. Thestereogenic carbon atoms of the cycloalkyl ring influence the absoluteand relative stereocofigurations of the compounds of the presentapplication. The binding properties of TRPV1 antagonists of the presentapplication are directly influenced by the absolute and relativestereoconfiguration of the stereocenters contained within the cycloalkylring.

The compounds and processes of the present application will be betterunderstood by reference to the following Examples, which are intended asan illustration of and not a limitation upon the scope of theapplication. Further, all citations herein are incorporated byreference.

Compounds of the application were named by ACD/ChemSketch version 5.01(developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada)or were given names consistent with ACD nomenclature. Alternatively,compounds were assigned names using ChemDraw Ultra 9.0 (or higherversion) (Cambridgesoft). The practice of assigning names to chemicalcompounds from structures, and of assigning chemical structures fromgiven chemical names is well known to those of ordinary skill in theart.

Preparation of Compounds

The compounds of this application can be prepared by a variety ofsynthetic procedures. Representative procedures are shown in, but arenot limited to, Schemes 1-14.

As outlined in Scheme 1, compounds of formula 5, wherein Ar₁, L₁, R₁,R₂, R₃, R₄, R₅ and n are defined in formula (I), which arerepresentative of compounds of the present application, may be preparedaccordingly. Compounds of formula 1, wherein R₁, R₂, R₃, R₄, R₅ and nare defined in formula (I) which may be obtained from commercial sourcesor may be prepared according to procedures known in the literature orthrough methods known to one skilled in the art, when treated withcompounds of formula 2 (N—N′-disuccuinimidyl carbonate), in a solventsuch as but not limited to acetonitrile will provide compounds offormula 3. Compounds of formula 3 when treated with a compound offormula 4, wherein L₁ and Ar₁ are defined in formula (I) which may beobtained from commercial sources or may be prepared from knownliterature procedures or through methods known to one skilled in theart, in a solvent such as but not limited to acetonitrile or THF willprovide compounds of formula 5.

Alternatively, compounds of formula 3 described in Scheme 1, whentreated with compounds of formula 6, wherein L₁ and Ar₁ are defined informula (I) which may be obtained from commercial sources or may beprepared according to procedures known in the literature or may beprepared according to methods known to one skilled in the art, in thepresence of a base such as but not limited to diisopropylethylamine ortriethylamine in a solvent such as but not limited to acetonitrile orTHF will provide compounds of formula 7 which are representative ofcompounds of the present application when Y₃ is —O—.

Alternatively when compounds of formula 1, wherein R₁, R₂, R₃, R₄, R₅,n, L₁ and Ar₁ are defined in formula (I), when treated with the compoundof formula 8 (20% phosgene in toluene) in the presence of DMAP (>2equivalents) in a solvent such as but not limited to dichloromethane,will provide compounds of formula 11. Compounds of formula 11 whentreated with compounds of formula 4, which are described in Scheme 1,will provide compounds of formula 5 which are representative ofcompounds of formula (I) when Y₃ is —NH—. Alternatively, compounds offormula 11 when treated with compounds of formula 6, which are describedin Scheme 2, will provide compounds of formula 7 which arerepresentative of compounds of formula (I) when Y₃ is —O—.

As outlined in Scheme 4, compounds of formula 12, wherein r is 1 or 2, sis 1, 2, 3 or 4 and Ar₁ is as defined in formula (I), when treated withO-methyl hydroxylamine hydrochloride in pyridine or a mixture ethanoland pyridine will provide compounds of formula 13. Compounds of formula13 when treated with Raney Nickel or a palladium catalyst such as 5-10%palladium under a pressurized atmosphere of hydrogen in a solvent suchas ethanol, will provide compounds of formula 14. Typical conditions forthe transformation of compounds of formula 13 into compounds of formula14 include shaking or stirring the mixture of compound of formula 13 andthe Raney-Nickel or a palladium catalyst under 40-70 psi of hydrogen atambient temperature for 1-4 hours followed by filtration of thecatalyst. Compounds of formula 14 when treated with compounds of formula3, described in Scheme 1, will provide compounds of formula 15 which arerepresentative of compounds of the present application. Alternatively,compounds of formula 14 may be obtained through a reductive amination ofcompounds of formula 12 with benzylamine using sodium borohydridefollowed by treatment of the product with palladium on carbon or anotherbenzyl reducing catalyst in the presence of hydrogen.

Alternatively compound of formula 14, wherein r is 1 or 2, s is 1, 2, 3or 4 and Ar₁ is as defined in formula (I), when treated with thecompound of formula 2 as defined in Scheme 1, will provide compounds offormula 16. Compounds of formula 16 when treated with compounds offormula 1, as defined in Scheme 1, will provide compounds of formula 15which are representative of compounds of the present application.

When compounds of formula 1, wherein R₁, R₂, R₃, R₄, R₅ and n aredefined in formula (I), and compounds of formula 16, wherein Ar₁ and L₁are defined in formula (I) are treated according to standard carboxylicacid amine coupling conditions known to one skilled in the art willprovide compounds of formula 17 which are representative of compounds ofthe present application wherein Y₃ is a bond. Standard carboxylic acidamine coupling conditions include stirring the mixture of the carboxylicacid and the amine with a coupling reagent such as but not limited to1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),1,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinicchloride (BOPCl),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) with or without an auxiliary reagent such as but not limited to1-hydroxy-7-azabenzotriazole (HOAT) or 1-hydroxybenzotriazole hydrate(HOBT) in a solvent such as but not limited to dichloromethane.

As outlined in Scheme 7, compounds of formula 23 which arerepresentative of heterocycles Ar₁, may be prepared as outlined.Compounds of formula 18 wherein R₉ is alkenyl, alkoxy, alkoxyalkoxy,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, alkynyl, cycloalkyl,cycloalkylalkyl, haloalkoxy, haloalkyl or halogen, and p is 0, 1, 2 or 3when treated with acrylonitrile and DABCO® under heated condition willprovide compounds of formula 19. Compounds of formula 18 may be obtainedfrom commercial sources or may be prepared according to procedures knownto one skilled in the art. Compounds of formula 19 when treated withaqueous sodium hydroxide under heated conditions will provide compoundsof formula 20. Compounds of formula 20 when heated in the presence ofDPPA and triethylamine in toluene followed by heating in the presence of6M hydrochloric acid will provide compounds of formula 21. Compounds offormula 21 when treated with O-methylhydroxylamine in pyridine or amixture of pyridine and ethanol will provide compounds of formula 22.Compounds of formula 22 when treated with an atmosphere of hydrogen inthe presence of Raney-nickel in a solvent such as methanol containinganhydrous ammonia gas will provide compounds of formula 23.Alternatively, compounds of formula 21 when treated with ammoniumacetate followed by treatment with sodium cyanoborohydride in a solventsuch as but not limited to THF will provide compounds of formula 23. Inaddition, the ketone of compound of formula 21, may be treated withbenzyl amine followed by the addition of sodium cyanoborohydride willprovide the benzyl protected amine. The benzyl protecting group may beremoved by treatment with an atmosphere of hydrogen and a palladiumcatalyst such as 10% palladium on carbon in a solvent such as methanolwith or without a catalytic amount of acetic acid to provide compoundsof formula 23.

As outlined in Scheme 8, compounds of formula 28 which arerepresentative of heterocycles Ar₁, may be prepared as outlined.Compounds of formula 24, wherein R₉ and p are as defined in Scheme 7which are available from commercial sources or may be prepared accordingto methods known to one skilled in the art, when treated with3-bromo-1-propyne and potassium carbonate in acetonitrile will providecompounds of formula 25. Compounds of formula 25 when treated withN-chlorosuccinimide and silver acetate in acetone under heatedconditions will provide compounds of formula 26. Compounds of formula 26when heated in a solvent such as but not limited to ethylene glycol willprovide compounds of formula 27. Compounds of formula 27 when treatedwith O-methylhydroxylamine in pyridine or a mixture of pyridine andethanol will provide the O-methyl oxime which when treated with anatmosphere of hydrogen in the presence of Raney-nickel in a solvent suchas methanol containing anhydrous ammonia gas will provide compounds offormula 28. Alternatively, compounds of formula 27 when treated withammonium acetate and sodium cyanoborohydride in a solvent such as butnot limited to THF will provide compounds of formula 28. In addition,the ketone may also be subjected to reductive amination conditions inthe presence of benzylamine followed by hydrogenation to remove thebenzyl group to provide compounds of formula 28, which may be treatedaccording to the procedures outlined above to generate compounds offormula (I).

As outlined in Scheme 9, compounds of formula 35 which arerepresentative of heterocycles Ar₁, may be prepared accordingly.Compounds of formula 29, wherein R₉ and p are defined in Scheme 7, whichmay be obtained from commercial sources or may be prepared according tomethods known to one skilled in the art, when treated with 3 equivalentsof methyl lithium in THF at about −70° C. then allowing the mixture towarm to ambient temperature will provide compounds of formula 30.Compounds of formula 30 when treated with diethyl oxalate and sodiumethoxide in ethanol under heated conditions will provide compounds offormula 31. The hydrolysis of the ester functional group of compounds offormula 31 with aqueous 12 N HCl in acetic acid under heated conditionswill to provide compounds of formula 32. Compounds of formula 32 whentreated with 10% palladium on carbon and an atmosphere of hydrogen inacetic acid heated to temperatures of about 70° C. will providecompounds of formula 33. Compounds of formula 33 when treated withoxalyl chloride and a catalytic amount of DMF in dichloromethane willprovide the acid chloride which when subjected to ammonia gas in dioxaneor concentrated ammonium hydroxide in dioxane or THF will providecompounds of formula 34. Compounds of formula 34 when treated withlithium aluminum hydride in THF under heated conditions will providecompounds of formula 35, which may be treated according to theprocedures outlined above to generate compounds of formula (I).

As outlined in Scheme 10, compounds of formula 42 which arerepresentative of heterocycles Ar₁, may be prepared accordingly.Compounds of formula 36 which are available from commercial sources ormay be obtained through methods known to one skilled in the art, whereinR₉ and p are as described above, when treated with oxetan 2-one (37) inacetonitrile under heated conditions will provide compounds of formula38. Compounds of formula 38 when treated with Eaton' reagent (7.7 weight% phosphorous pentoxide in methane sulfonic acid) under heatedconditions will provide compounds of formula 39. Compounds of formula 39when treated with reagents that will protect amine functional groups asknown to one skilled in the art or as outlined in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley& Sons, New York (1999) will provide compounds of formula 40. Compoundsof formula 40 when treated with O-methylhydroxylamine in pyridine willprovide compounds of formula 41. Compounds of formula 41 when treatedwith an atmosphere of hydrogen in the presence of Raney-nickel in asolvent such as methanol containing anhydrous ammonia gas will providecompounds of formula 42, which may be treated according to theprocedures outlined above to generate compounds of formula (I).

As outlined in Scheme 11, compounds of formula 36 which arerepresentative of heterocycles Ar₁, may be prepared accordingly.Alternatively, compounds of formula 36 when treated with compounds offormula 43 in the presence of a base such as potassium carbonate insolvents such as but not limited to dichloromethane or acetonitrile willprovide compounds of formula 44. Compounds of formula 44 when treatedwith sodium tert-butoxide in DMF will provide compounds of formula 45.Compounds of formula 45 when treated with trifluoroacetic acid indichloroethane under heated conditions will provide compounds of formula39. Similarly, compounds of formula 39 when treated according to theprocedures outlined in Scheme 10 will generate compounds of formula 42,which may be treated according to the procedures outlined above togenerate compounds of formula (I).

As outlined in Scheme 12, compounds of formula 51 which arerepresentative of heterocycles Ar₁, may be prepared accordingly.Compounds of formula 46 which may be obtained through commercial sourcesor may be generated through methods known to one skilled in the art,wherein R₉ and p are as defined above, when heated in the presence of anatmosphere of hydrogen and 10% palladium on carbon in a solvent such asethanol will generate compounds of formula 47. Compounds of formula 48when treated with a reagent that will protect an amine functional groupas described in Scheme 10 will provide compounds of formula 48.Compounds of formula 48 when treated with sodium, lithium or potassiumhydroxide in an aqueous alcoholic solvent will provide compounds offormula 49. Compounds of formula 49 when treated with diphenylphosphorylazide and triethylamine in tert-butanol under heated conditions willprovide compounds of formula 50. Compounds of formula 50 when treatedwith hydrochloric in acetic acid or trifluoroacetic acid indichloromethane will provide compounds of formula 51, which may betreated according to the procedures outlined above to generate compoundsof formula (I).

As outlined in Scheme 13, compounds of formula 55 which arerepresentative of heterocycles Ar₁, may be prepared accordingly.Similarly, compounds of formula 51 when treated with an atmosphere ofhydrogen in the presence of 5% palladium on carbon in a solvent such asacetic acid will provide compounds of formula 52. The amine functionalgroup of compounds of formula 52 may be protected through methods knownto one skilled in the art or as described in the literature as listed inScheme 10, will provide compounds of formula 53. Compounds of formula 53when treated with ammonia gas in methanol in a sealed vessel underheated conditions will generate compounds of formula 54. The treatmentof compounds of formula 54 with lithium aluminum hydride in THF undermild heated conditions will generate compounds of formula 55, which maybe treated according to the procedures outlined above to generatecompounds of formula (I).

As outlined in Scheme 14, compounds of formula compounds of formula 58,wherein R₃, R₄ and R₅ are defined in formula (I), which are used in thepreparation of compounds of formula (I) may be obtained from commercialsources or may be prepared accordingly. Compounds of formula 56 whichcontain both a hydroxyl and an amine functional group when subjected to1300 psi of hydrogen gas in the presence of Raney-nickel and sodiumhydroxide in ethanol at about 80° C. will provide compounds of formula57. The hydroxyl group of compounds of formula 57 may be protectedaccording to conditions known to one skilled in the art or throughmethods outlined in T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, 3rd edition, John Wiley & Sons, New York (1999) toprovide compounds of formula 58, which may be treated according to theprocedures outlined above to generate compounds of formula (I).

It is understood that the foregoing schemes are described forillustrative purposes and that routine experimentation, includingappropriate manipulation of the sequence of the synthetic route,protection of any chemical functionality that are not compatible withthe reaction conditions and the removal of such protecting groups areincluded in the scope of the application.

EXAMPLES

The following Examples are intended as an illustration of and not alimitation upon the scope of the application as defined in the appendedclaims.

Example 1N-(3,4-Dihydro-2H-chromen-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 1A 2H-Chromene-3-carbonitrile

A microwave vessel was charged with 2-hydroxybenzaldehyde (Aldrich, 3.0mL, 28.6 mmol), acrylonitrile (9.4 mL, 143 mmol) and1,4-diazabicyclo[2.2.2]octane (0.80 g, 7.2 mmol), and heated in amicrowave Personal Chemistry at 90° C. for 13 hours. Sodium hydroxide(1N, 200 mL) was added and the mixture was extracted twice with ethylacetate (200 mL), and the combined organic layer washed with brine,dried with anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. The residue was chromatographed on silica gel elutingwith 0-to-20% ethyl acetate in hexane providing the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 4.88 (d, J=1.36 Hz, 2H), 6.90 (d, J=8.14Hz, 1H), 7.01 (td, J=7.46, 1.01 Hz, 1H), 7.30 (m, 2H), 7.58 (s, 1H). MS(DCI) m/z 175.05 (M+NH₄)⁺.

Example 1B 2H-Chromene-3-carboxylic acid

Example 1A (3.543 g, 22.5 mmol), 50 w % sodium hydroxide (25 mL) andwater (50 mL) were heated to reflux for 4 hours. After cooling toambient temperature, water was added (500 mL) and the mixture wasacidified with 6N hydrochloric acid (80 mL) to precipitate the product.The solids were collected by filtration, rinsed with water, and freezedried to obtain the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 4.91(d, J=1.36 Hz, 2H), 6.84 (d, J=8.14 Hz, 1H), 6.95 (td, J=7.46, 1.01 Hz,1H), 7.26 (td, J=7.80, 1.70 Hz, 1H), 7.32 (dd, J=7.46, 1.70 Hz, 1H),7.44 (s, 1H), 12.82 (br s, 1H). MS (EI) m/z 176.10 (M)⁺.

Example 1C Chroman-3-one

Example 1B (3.472 g, 19.7 mmol) was dissolved in dichloromethane (45 mL)to which was added triethylamine (3.5 mL) and diphenylphosphoryl azide(5.97 g, 21.7 mmol) in toluene (20 mL). The flask was equipped with aDean-Stark trap and the mixture was heated to reflux. Toluene (45 mL)was added after one hour and the mixture was reflux for an 2 additionalhours after which it was cooled to ambient temperature. 6N hydrochloricacid (50 mL) and toluene (20 mL) were added and the biphasic mixturerefluxed for 3.5 hours followed by cooling to ambient temperature. Ethylacetate (100 mL) and water (100 mL) were added, and the separatedorganic layer was washed sequentially with saturated sodium bicarbonate(2×100 mL), brine, dried over anhydrous sodium sulfate and filtered. Thesolution was concentrated under reduced pressure and chromatographed onsilica gel eluting with 0-to-40% ethyl acetate in hexane to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.68 (s, 2H), 4.46 (s,2H), 7.04 (m, 2H), 7.23 (m, 2H). MS (DCI) m/z 148.04 (M+NH₄—H₂O)⁺.

Example 1D Chroman-3-one O-methyl oxime

Methoxylamine hydrochloride (1.23 g, 14.8 mmol) was added to a solutionof Example 1C (1.99 g, 13.4 mmol) in pyridine (30 mL) and stirredovernight at ambient temperature. The mixture was concentrated to ayellow residue and ethyl acetate (200 mL) and 1N hydrochloric acid (200mL) were added. The organic layer was washed with brine, dried withanhydrous sodium sulfate and filtered. The solvent was concentratedunder reduced pressure and the residue chromatographed on silica geleluting with 0-to-20% ethyl acetate in hexane to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.72 (s, 2H), 3.85 (s, 3H),4.51 (s, 2H), 6.89 (dd, J=8.14, 1.36 Hz, 1H), 6.96 (td, J=7.46, 1.36 Hz,1H), 7.14 (m, 1H), 7.21 (d, J=7.46 Hz, 1H). MS (DCI) m/z 178.07 (M+H)⁺.

Example 1E Chroman-3-amine

Example 1D (2.027 g, 11.4 mmol), Raney nickel (10.0 g), and 20% ammoniain anhydrous methanol (20 mL) were shaken under an atmosphere ofhydrogen (60 psi) for 3 hours at ambient temperature. The catalyst wasremoved by filtration and the solvent evaporated under reduced pressureto afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.61 (brs, 2H), 2.46 (dd, J=16.28, 9.16 Hz, 1H), 2.87 (dd, J=15.94, 3.73 Hz,1H), 3.10 (m, 1H), 3.57 (dd, J=10.17, 8.82 Hz, 1H), 4.06 (ddd, J=10.26,3.48, 1.86 Hz, 1H), 6.72 (dd, J=8.48, 1.35 Hz, 1H), 6.80 (td, J=7.46,1.36 Hz, 1H), 7.04 (m, 2H). MS (DCI) m/z 150.07 (M+H)⁺.

Example 1F 8-Amino-1,2,3,4-tetrahydronaphthalen-2-ol

A hydrogenation reaction vessel was charged with 8-aminonaphthalen-2-ol(Aldrich, 5.0 g, 31.4 mmol), 50% w/w sodium hydroxide (0.2 g, 2.5 mmol)and Raney nickel (slurry in water, 40% weight load, 2.0 g) in ethanol(100 mL). The vessel was purged with hydrogen gas several times beforesealing under a hydrogen atmosphere at a pressure of 1300 psi followedby heating to 85° C. After 6 hours the mixture was filtered, and thefiltrate was concentrated under reduced pressure to afford the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.44-1.68 (m, 1H), 1.79-1.94(m, 1H), 2.20 (dd, J=16.48, 7.63 Hz, 1H), 2.56-2.85 (m, 3H), 3.85-3.99(m, 1H), 4.63 (s, 2H), 4.75 (d, J=4.12 Hz, 1H), 6.30 (d, J=7.48 Hz, 1H),6.44 (d, J=7.78 Hz, 1H), 6.78 (t, J=7.63 Hz, 1H). ¹³C NMR (126 MHz,DMSO-d₆) δ ppm 27.35, 31.41, 33.36, 65.81, 111.35, 116.48, 119.13,125.53, 136.00, 146.12. MS (DCI) m/z 164.06 (M+H)⁺.

Example 1G7-(tert-Butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-amine

A mixture of Example 1F (2.33 g, 14.3 mmol),tert-butylchlorodimethylsilane (2.6 g, 17.2 mmol) and imidazole (2.9 g,42.3 mmol) in dichloromethane (40 mL) were stirred at ambienttemperature overnight. The mixture was then washed several times withwater and once with brine. The organic layer was separated and driedover anhydrous sodium sulfate. Filtration and concentration afforded thetitle compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.09 (s, 6H), 0.88 (s,9H), 1.63 (m, 1H), 1.82 (m, 1H), 2.24 (m, 1H), 2.75 (m, 3H), 4.11 (m,1H), 4.7 (br s, 2H), 6.28 (d, J=7.4 Hz, 1H), 6.42 (d, J=7.8 Hz, 1H),6.77 (dd, J=7.8, 7.4 Hz, 1H). MS (ESI) m/z 278 (M+H)⁺.

Example 1HN-(3,4-Dihydro-2H-chromen-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

To di-(N-succinimidyl)carbonate (Fluka, 538 mg, 2.1 mmol) inacetonitrile (5 mL) was added Example 1G (555 mg, 2.0 mmol) inacetonitrile (10 mL) and pyridine (0.17 mL, 2.1 mmol). The mixture wasstirred for 15 minutes at ambient temperature. Example 1E (298 mg, 2.0mmol) and diisopropylethylamine (1.05 mL, 6.0 mmol) were added and themixture stirred for 30 minutes. The mixture was filtered through asilica gel plug, rinsed with 1/1 ethyl acetate/hexane and concentratedunder reduced pressure to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(chroman-3-yl)-urea.This intermediate was dissolved in tetrahydrofuran (20 mL),tetrabutylammonium fluoride (1.0M in THF, 6.0 mL, 6.0 mmol) was added,and the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and chromatographed on silicagel eluting with ethyl acetate and concentrated under reduced pressure.The residue was dissolved in ethyl acetate (200 mL) and washedsequentially with 1N sodium hydroxide (200 mL), water (200 mL) andbrine. The organic layer was dried with anhydrous sodium sulfate,filtered, concentrated under reduced pressure and vacuum dried overnightto afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.56 (m,1H), 1.84 (m, 1H), 2.27 (m, 1H), 2.74 (m, 4H), 3.09 (dd, J=16.95, 3.09Hz, 1H), 3.89 (m, 1H), 4.02 (m, 1H), 4.12 (m, 2H), 4.82 (d, J=4.07 Hz,1H), 6.69 (d, J=7.12 Hz, 1H), 6.85 (m, 3H), 6.97 (t, J=7.80 Hz, 1H),7.11 (m, 2H), 7.61 (s, 1H), 7.69 (d, J=7.46 Hz, 1H). MS (ESI) m/z 339.10(M+H)⁺. Calcd for C₂₀H₂₂N₂O₃.0.15 EtOAc: C, 70.37; H, 6.65; N, 7.97.Found: C, 70.34; H, 6.70; N, 8.04.

Example 2N-(8-tert-Butyl-3,4-dihydro-2H-chromen-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 2A 8-tert-Butyl-2H-chromene-3-carbonitrile

3-tert-butyl-2-hydroxybenzaldehyde (Aldrich, 4.0 mL, 23.4 mmol),acrylonitrile (7.7 mL, 117 mmol), and 1,4-diazabicyclo[2.2.2]octane(0.66 g, 5.8 mmol) were heated in a microwave Personal Chemistry at 95°C. for 5 hours. Sodium hydroxide (1N, 200 mL) was added and the mixturewas extracted twice with ethyl acetate (200 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered, and concentrate under reduced pressure. The residue waschromatographed on silica gel eluting with 0-to-30% ethyl acetate inhexane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.31 (s, 9H), 4.85 (d, J=1.36 Hz, 2H), 6.97 (t, J=7.63 Hz, 1H), 7.16(dd, J=7.63, 1.53 Hz, 1H), 7.29 (dd, J=7.80, 1.70 Hz, 1H), 7.58 (s, 1H).MS (DCI) m/z 231.10 (M+NH₄)⁺.

Example 2B 8-tert-Butyl-2H-chromene-3-carboxylic acid

Example 2A (2.25 g, 12.0 mmol), 50 w % sodium hydroxide (25 mL), water(75 mL) and ethanol (50 mL) were heated at reflux for 6 hours. Themixture was cooled, water (500 mL) was added and the mixture wasacidified with 6N hydrochloric acid (80 mL) to afford a precipitate. Themixture was filtered, rinsed with water, and freeze-dried to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.32 (s, 9H), 4.86 (d,J=1.36 Hz, 2H), 6.91 (t, J=7.63 Hz, 1H), 7.21 (dd, J=11.53, 1.70 Hz,1H), 7.23 (dd, J=11.70, 1.53 Hz, 1H), 7.43 (t, J=1.19 Hz, 1H), 12.79 (brs, 1H). MS (DCI) m/z 250.10 (M+NH₄)⁺.

Example 2C 8-tert-Butylchroman-3-one

Example 2B (3.865 g, 16.6 mmol) was dissolved in dichloromethane (45mL). Triethylamine (3.5 mL) and diphenylphosphoryl azide (5.04 g, 18.3mmol) in toluene (20 mL) were added. The flask was equipped with aDean-Stark trap and heated to reflux. Toluene (45 mL) was added afterone hour, and the mixture continued to reflux for 1.5 additional hoursafter which it was allowed to cool to ambient temperature. Hydrochloricacid (6N, 50 mL) and toluene (10 mL) were added and the biphasic mixturewas heated at reflux for 2 hours then cooled to ambient temperature.Ethyl acetate (100 mL) and water (100 mL) were added, and the organiclayer was washed twice with saturated sodium bicarbonate (100 mL), thenwith brine, dried over anhydrous sodium sulfate and filteredconcentrated under reduced pressure and purified on silica gel elutingwith 0-to-30% ethyl acetate in hexane afforded the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.36 (s, 9H), 3.66 (s, 2H), 4.43 (s, 2H),6.99 (t, J=7.63 Hz, 1H), 7.08 (dd, J=7.29, 1.19 Hz, 1H), 7.19 (dd,J=7.80, 1.36 Hz, 1H). MS (DCI) m/z 204.10 (M+NH₄—H₂O)⁺.

Example 2D 8-tert-Butylchroman-3-one O-methyl oxime

Methoxylamine hydrochloride (1.15 g, 13.7 mmol) was added to a solutionof Example 2C (2.547 g, 12.5 mmol) in pyridine (3 0 mL) and the mixturewas stirred overnight at ambient temperature. The mixture wasconcentrated under reduced pressure, and ethyl acetate (200 mL) and 1Nhydrochloric acid (200 mL) were added. The separated organic layer waswashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was chromatographed onsilica gel eluting with 0-to-20% ethyl acetate in hexane to afford thetitle compound. MS (DCI) m/z 234.12 (M+H)⁺.

Example 2E 8-tert-Butylchroman-3-amine

Example 2D (1.870 g, 8.02 mmol), Raney nickel (9.0 g), and 20% ammoniain methanol (40 mL) were shaken under hydrogen (60 psi) for 3 hours atambient temperature. The catalyst was removed by filtration and thesolvent was removed under reduced pressure to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.31 (s, 9H), 1.63 (br s, 2H), 2.46 (m,1H), 2.89 (m, 1H), 3.09 (m, 1H), 3.56 (dd, J=10.17, 8.82 Hz, 1H), 4.14(ddd, J=10.26, 3.31, 1.70 Hz, 1H), 6.73 (t, J=7.46 Hz, 1H), 6.88 (d,J=6.10 Hz, 1H), 7.00 (dd, J=7.63, 1.53 Hz, 1H). MS (DCI) m/z 206.08(M+H)⁺.

Example 2FN-(8-tert-Butyl-3,4-dihydro-2H-chromen-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

To di-(N-succinimidyl)carbonate (538 mg, 2.1 mmol) in acetonitrile (5mL) was added Example 1G (555 mg, 2.0 mmol) in acetonitrile (10 mL) andpyridine (0.17 mL, 2.1 mmol). The mixture was stirred for 15 minutes atambient temperature. Example 2E (411 mg, 2.0 mmol) anddiisopropylethylamine (1.05 mL, 6.0 mmol) were added and the mixturestirred for an additional 30 minutes. The mixture was filtered through asilica gel plug, rinsed with 1/1 ethyl acetate/hexane, and concentratedunder reduced pressure to afford1-(8-tert-butylchroman-3-yl)-3-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL) followed bythe addition of tetrabutylammonium fluoride (1.0M in THF, 6.0 mL, 6.0mmol) and the mixture stirred overnight at ambient temperature. Ethylacetate (200 mL) was added and the organic layer was washed sequentiallywith 1N sodium hydroxide (200 mL), water (200 mL), and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was chromatographed onsilica gel eluting with 0-to-5% methanol in ethyl acetate to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.34 (s, 9H), 1.58 (m,1H), 1.85 (m, 1H), 2.29 (dd, J=16.28, 7.80 Hz, 1H), 2.72 (m, 4H), 3.11(dd, J=16.28, 5.43 Hz, 1H), 3.90 (m, 1H), 3.98 (m, 1H), 4.10 (m, 1H),4.17 (d, J=10.17 Hz, 1H), 4.82 (d, J=3.73 Hz, 1H), 6.71 (d, J=8.14 Hz,1H), 6.74 (dd, J=7.12, 3.05 Hz, 1H), 6.80 (t, J=7.63 Hz, 1H), 6.96 (dd,J=7.46, 1.36 Hz, 1H), 6.98 (t, J=7.80 Hz, 1H), 7.06 (dd, J=7.80, 1.70Hz, 1H), 7.66 (m, 2H). MS (ESI) m/z 395.24 (M+H)⁺. Calcd forC₂₄H₃₀N₂O₃.0.09 H₂O: C, 72.77; H, 7.68; N, 7.07. Found: C, 72.79; H,7.79; N, 7.08.

Example 3N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(7-methoxy-3,4-dihydro-2H-chromen-3-yl)ureaExample 3A 7-Methoxy-2H-chromene-3-carbonitrile

2-Hydroxy-4-methoxybenzaldehyde (Aldrich, 5.0 g, 32.9 mmol),acrylonitrile (11 mL, 164 mmol), and 1,4-diazabicyclo[2.2.2]octane (0.92g, 8.2 mmol) were heated in a microwave Personal Chemistry at 95° C. for5 hours. Sodium hydroxide (200 mL) was added and the mixture wasextracted with ethyl acetate (200 mL) and brine. The organic layer wasdried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. Chromatography on silica gel eluting with 0-to-50%ethyl acetate in hexane afforded the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.77 (s, 3H), 4.84 (d, J=1.36 Hz, 2H), 6.50 (d, J=2.71Hz, 1H), 6.61 (dd, J=8.48, 2.71 Hz, 1H), 7.21 (d, J=8.48 Hz, 1H), 7.52(s, 1H). MS (DCI) m/z 205.07 (M+NH₄)⁺.

Example 3B 7-Methoxy-2H-chromene-3-carboxylic acid

Example 3A (2.25 g, 12.0 mmol), 50 w % sodium hydroxide (25 mL), water(50 mL), and ethanol (25 mL), were heated to reflux for 3 hours. Themixture was cooled and water (300 mL) was added. The mixture wasacidified with 1N hydrochloric acid (100 mL) to afford a precipitate.The mixture was filtered and the solids were rinsed with water andfreeze-dried to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δppm 3.75 (s, 3H), 4.87 (d, J=1.36 Hz, 2H), 6.45 (d, J=2.71 Hz, 1H), 6.55(dd, J=8.31, 2.54 Hz, 1H), 7.25 (d, J=8.48 Hz, 1H), 7.41 (s, 1H), 12.62(br s, 1H). MS (DCI) m/z 206.87 (M+H)⁺.

Example 3C 7-Methoxychroman-3-one

Example 3B (1.928 g, 9.35 mmol) was dissolved in dichloromethane (25 mL)followed by the addition of triethylamine (1.7 mL) anddiphenylphosphoryl azide (2.83 g, 10.3 mmol) in toluene (10 mL). Theflask was equipped with a Dean-Stark trap and the solution was refluxed.After one hour, toluene (25 mL) was added, and the mixture continued toreflux for 2 hours followed by cooling to ambient temperature.Hydrochloric acid (6N, 20 mL), was added and the mixture was heated toreflux for an additional 3 hours after which it was cooled. Ethylacetate (100 mL) and water (100 mL) were added, and the separatedorganic layer was washed twice with saturated sodium bicarbonate (100mL), once with brine, dried over anhydrous sodium sulfate and filtered.Concentration under reduced pressure and chromatography on silica geleluting with 40-to-90% dichloromethane in hexane afforded the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.59 (s, 2H), 3.73 (s, 3H),4.44 (s, 2H), 6.64 (m, 2H), 7.10 (d, J=8.82 Hz, 1H). MS (DCI) m/z 178.99(M+H)⁺.

Example 3D 7-Methoxychroman-3-one O-methyl oxime

Methoxylamine hydrochloride (459 mg, 5.49 mmol) was added to a solutionof Example 3C (890 mg, 4.99 mmol) in pyridine (2 0 mL) and the mixturewas stirred overnight at ambient temperature. The mixture wasconcentrated under reduced pressure, taken up in ethyl acetate (100 mL)and 1N hydrochloric acid (100 mL). The separated organic layer waswashed with brine, filtered, and dried over anhydrous sodium sulfate.Concentration and chromatography on silica gel eluting with 0-to-20%ethyl acetate in hexane afforded the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.64 (s, 2H), 3.70 (s, 3H), 3.85 (s, 3H), 4.49 (s, 2H),6.47 (d, J=2.72 Hz, 1H), 6.57 (dd, J=8.48, 2.38 Hz, 1H), 7.10 (d, J=8.48Hz, 1H). MS (DCI) m/z 208.05 (M+H)⁺.

Example 3E 7-Methoxychroman-3-amine

Example 3D (829 mg, 4.0 mmol), Raney nickel (5.0 g) and 20% ammonia inmethanol (30 mL) were shaken under hydrogen (60 psi) for 3 hours atambient temperature. The catalyst was removed by filtration and thesolvent was evaporated under reduced pressure affording the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.61 (br s, 2H), 2.37 (dd,J=15.43, 8.99 Hz, 1H), 2.79 (dd, J=15.43, 4.24 Hz, 1H), 3.06 (m, 1H),3.54 (dd, J=10.18, 8.82 Hz, 1H), 3.67 (s, 3H), 4.04 (ddd, J=10.26, 3.31,1.70 Hz, 1H), 6.30 (d, J=2.71 Hz, 1H), 6.41 (dd, J=8.31, 2.54 Hz, 1H),6.92 (d, J=8.48 Hz, 1H). MS (DCI) m/z 180.07 (M+H)⁺.

Example 3FN-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(7-methoxy-3,4-dihydro-2H-chromen-3-yl)urea

To a suspension of di(N-succinimidyl)carbonate (409 mg, 1.60 mmol) inacetonitrile (5 mL) was added Example 1G (422 mg, 1.52 mmol) inacetonitrile (10 mL) and pyridine (0.13 mL, 1.60 mmol). After 15 minutesat ambient temperature, Example 3E (272 mg, 1.52 mmol) anddiisopropylethylamine (0.79 mL, 4.56 mmol) were added and the mixturestirred for 30 minutes. The mixture was filtered through a silica gelplug, rinsed with 1/1 ethyl acetate/hexane, and concentrated underreduced pressure to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(7-methoxychroman-3-yl)urea.The residue was dissolved in tetrahydrofuran (30 mL), tetrabutylammoniumfluoride (1.0M in THF, 3.04 mL, 3.04 mmol) was added and the mixturestirred overnight at ambient temperature. The mixture was concentratedunder reduced pressure and the residue was chromatographed on silica geleluting with 0-to-10% methanol in ethyl acetate. The resulting solid wassuspended in methanol (20 mL) which was sonicated after which water (200mL) was added. The sonication was repeated and the solids were collectedby filtration, rinsed with water, and freeze-dried to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.56 (m, 1H), 1.84 (m, 1H),2.28 (m, 1H), 2.59 (m, 1H), 2.76 (m, 3H), 3.00 (dd, J=16.10, 5.26 Hz,1H), 3.70 (s, 3H), 3.89 (m, 1H), 4.01 (m, 1H), 4.10 (m, 2H), 4.82 (d,J=4.07 Hz, 1H), 6.40 (d, J=2.37 Hz, 1H), 6.49 (dd, J=8.31, 2.54 Hz, 1H),6.69 (d, J=7.46 Hz, 1H), 6.85 (d, J=7.46 Hz, 1H), 6.97 (t, J=7.80 Hz,1H), 7.00 (d, J=8.14 Hz, 1H), 7.61 (s, 1H), 7.69 (d, J=7.46 Hz, 1H). MS(ESI) m/z 369.16 (M+H)⁺. Calcd for C₂₁H₂₄N₂O₄.0.17 H₂O: C, 67.90; H,6.60; N, 7.54. Found: C, 67.92; H, 6.67; N, 7.41.

Example 4N-(6-Chloro-3,4-dihydro-2H-chromen-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 4A 6-Chlorochroman-3-one

To a solution of 6-chloro-2H-chromene-3-carboxylic acid (Avocado, 4.90g, 23.3 mmol) in dichloromethane (50 mL) was added triethylamine (4 mL)and diphenylphosphoryl azide (7.04 g, 25.6 mmol) in toluene (20 mL). Theflask was equipped with a Dean-Stark trap, and the mixture was heated toreflux. After 1.5 hours, toluene (50 mL) was added and the mixturecontinued to reflux for 2.5 hours and was then cooled to ambienttemperature. Hydrochloric acid (6N, 40 mL) was added, and the biphasicmixture was heated at reflux for 3.5 hours then cooled to ambienttemperature. Ethyl acetate (200 mL) and water (200 mL) were added andthe separated organic layer was washed sequentially with saturatedsodium bicarbonate (2×200 mL) followed by brine. The organic layer wasdried over anhydrous sodium sulfate, filtered, concentrate under reducedpressure, and chromatographed on silica gel eluting with 10-to-60%dichloromethane in hexane to afford the title compound. MS (DCI) m/z181.97 (M+H)⁺.

Example 4B 6-Chlorochroman-3-amine

Example 4A (1.29 g, 7.06 mmol) was dissolved in isopropyl alcohol (12 5mL) and ammonium acetate (16.34 g, 212 mmol) was added. The mixture wasstirred for one hour at ambient temperature. Sodium cyanoborohydride(1.55 g, 24.7 mmol) was added and the mixture refluxed for one hour, andwas cooled. After quenching with 3N sodium hydroxide (70 mL), themixture was extracted twice with tert-butyl methyl ether (100 mL), andconcentrate under reduced pressure. Ethyl acetate (100 mL) was added,and the mixture was extracted with 1N hydrochloric acid (3×70 mL). Theacidic aqueous extracts were combined, and 3N sodium hydroxide (90 mL)was added. The resulting aqueous solution was extracted twice with ethylacetate (200 mL). The three ethyl acetate layers were combined andwashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.71 (br s, 2H), 2.46 (dd, J=15.94, 8.48 Hz,1H), 2.88 (dd, J=15.26, 4.75 Hz, 1H), 3.09 (m, 1H), 3.60 (dd, J=10.85,8.48 Hz, 1H), 4.07 (ddd, J=10.43, 3.48, 2.03 Hz, 1H), 6.75 (d, J=8.81Hz, 1H), 7.08 (dd, J=8.48, 2.71 Hz, 1H), 7.12 (m, 1H). MS (DCI) m/z184.01 (M+H)⁺.

Example 4CN-(6-Chloro-3,4-dihydro-2H-chromen-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

Di(N-succinimidyl)carbonate (546 mg, 2.13 mmol) was suspended inacetonitrile (5 mL) followed by the addition of Example 1G (563 mg, 2.03mmol) in acetonitrile (5 mL) and pyridine (0.17 mL, 2.13 mmol). Themixture stirred for 15 minutes at ambient temperature followed by theaddition of Example 4B (373 mg, 2.03 mmol) in acetonitrile (10 mL) anddiisopropylethylamine (1.06 mL, 6.09 mmol). The mixture stirred for 30minutes was concentrated under reduced pressure and chromatographed onsilica gel eluting with 0-to-40% ethyl acetate in hexane to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(6-chlorochroman-3-yl)urea.The intermediate was dissolved in tetrahydrofuran (30 mL), andtetrabutylammonium fluoride (1.0M in THF, 4.06 mL, 4.06 mmol) was added,and the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and chromatographed on silicagel eluting with 0-to-10% methanol in ethyl acetate. The residue wasdissolved in methanol (20 mL), sonicated and water (200 mL) was added.The sonication was repeated, and the solids were collected byfiltration, rinsed with water, and freeze-dried to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.57 (m, 1H), 1.83 (m, 1H),2.27 (dd, J=16.45, 7.63 Hz, 1H), 2.74 (m, 4H), 3.10 (dd, J=16.95, 4.74Hz, 1H), 3.88 (m, 1H), 4.09 (m, 3H), 4.81 (d, J=4.07 Hz, 1H), 6.69 (d,J=7.46 Hz, 1H), 6.86 (m, 2H), 6.98 (t, J=7.80 Hz, 1H), 7.15 (dd, J=8.81,2.71 Hz, 1H), 7.21 (d, J=2.71 Hz, 1H), 7.58 (s, 1H), 7.69 (d, J=7.80 Hz,1H). MS (ESI) m/z 373.11 (M+H)⁺. Calcd for C₂₀H₂₁Cl₁N₂O₃.0.78 H₂O: C,62.09, H, 5.88; N, 7.24. Found: C, 62.09; H, 5.90; N, 7.19.

Example 5N-(8-tert-Butyl-3,4-dihydro-2H-chromen-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 5A 1-tert-Butyl-2-(prop-2-ynyloxy)benzene

2-tert-butylphenol (Aldrich, 15.02 g, 15.4 ml, 100 mmol), propargylbromide (80% in toluene, 14.3 ml, 128 mmol) and potassium carbonate(17.66 g, 128 mmol) were stirred together in acetonitrile (200 mL) for 5days at ambient temperature. The solvent was removed under reducedpressure, and the residue taken into water and extracted with diethylether. The organic layers were combined, dried with magnesium sulfate,filtered, and the solvent evaporated under reduced pressure to affordthe title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.39 (s, 9H), 2.48 (t,J=2.37 Hz, 1H), 4.73 (d, J=2.37 Hz, 2H), 6.90-6.98 (m, 2H), 7.15-7.22(m, 1H), 7.30 (dd, J=7.80, 1.70 Hz, 1H). MS (DCI) m/z 206 (M+NH₄)⁺.

Example 5B 1-tert-Butyl-2-(3-chloroprop-2-ynyloxy)benzene

To a solution of Example 5A (18.86 g, 100 mmol) in acetone (400 mL) wasadded N chlorosuccinimide (16.02 g, 120 mmol) and silver acetate (1.67g, 10 mmol) and the mixture was heated at reflux for 4 hours. Aftercooling, the silver salts were removed by filtration and the filtrateevaporated under reduced pressure. The residue was taken up in diethylether, washed with water and saturated aqueous sodium bicarbonate, driedwith magnesium sulfate, filtered, and the solvent was removed underreduced pressure to afford the title compound. ¹H NMR (300 MHz, CDCl₃) δppm 1.38 (s, 9H), 4.73 (s, 2H), 6.91-6.97 (m, 2H), 7.19 (td, J=7.71,1.86 Hz, 1H), 7.30 (dd, J=7.97, 1.53 Hz, 1H). MS (DCI) m/z 223 (M+H)⁺.

Example 5C 8-tert-Butylchroman-4-one

Example 5B (25.8 g) in ethylene glycol (250 mL) was heated to reflux for4 hours. The mixture was cooled, poured into water, and extracted withdiethyl ether. The organic layers were combined, washed sequentiallywith 1N sodium hydroxide and saturated ammonium carbonate, dried withmagnesium sulfate, and filtered. Removal of solvent under reducedpressure gave a residue which was taken up in 1/1 dichloromethane/hexaneand filtered through a pad of silica gel. The filtrate was evaporatedunder reduced pressure to afford the title compound. ¹H NMR (300 MHz,CDCl₃) δ ppm 1.39 (s, 9H), 2.79-2.85 (m, 2H), 4.51-4.58 (m, 2H), 6.95(t, J=7.80 Hz, 1H), 7.47 (dd, J=7.63, 1.86 Hz, 1H), 7.81 (dd, J=7.80,1.70 Hz, 1H). MS (DCI) m/z 205 (M+H)⁺.

Example 5D 8-tert-Butylchroman-4-one O-methyl oxime

Example 5C (13.51 g, 66 mmol) was dissolved in pyridine (100 mL).Methoxylamine hydrochloride (10 g, 120 mmol) was added and the mixturestirred for 16 hours at ambient temperature. The pyridine was removedunder reduced pressure, and the residue partitioned between water anddiethyl ether. The aqueous layer was extracted with diethyl ether, andthe combined organic layers were washed with 1N sodium hydroxide and 1Nhydrochloric acid, dried with magnesium sulfate, and filtered. Thesolvent was removed under reduced pressure afford the title compound. ¹HNMR (300 MHz, CDCl₃) δ ppm 1.36 (s, 9H), 2.91 (t, J=6.27 Hz, 2H), 3.98(s, 3H), 4.18 (t, J=6.27 Hz, 2H), 6.87 (t, J=7.80 Hz, 1H), 7.21-7.27 (m,1H), 7.79 (dd, J=7.80, 1.70 Hz, 1H). MS (DCI) m/z 234 (M+H)⁺.

Example 5E 8-tert-Butylchroman-4-amine

Example 5D (14.44 g, 61.9 mmol), 10% palladium on carbon (1.5 g), and20% ammonia in methanol (400 mL) were shaken under hydrogen (60 psi) for2.5 hours at ambient temperature. The catalyst was removed by filtrationand the solvent evaporated under reduced pressure to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.34-1.37 (m, 9H), 1.90 (td,J=9.16, 4.07 Hz, 1H), 2.10-2.25 (m, 1H), 4.11 (t, J=5.09 Hz, 1H),4.22-4.29 (m, 2H), 6.81-6.89 (m, 1H), 7.14-7.24 (m, 2H). MS (DCI) m/z206 (M+H)⁺.

Example 5FN-(8-tert-Butyl-3,4-dihydro-2H-chromen-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

To a solution of di(N-succinimidyl)carbonate (408 mg, 1.59 mmol) inacetonitrile (5 mL) was added Example 1G (421 mg, 1.52 mmol) dissolvedin acetonitrile (5 mL) and pyridine (0.13 mL, 1.59 mmol) and the mixturestirred for 15 minutes at ambient temperature. Example 5E (311 mg, 1.52mmol) dissolved in acetonitrile (10 mL) and diisopropylethylamine (0.79mL, 4.55 mmol) was added and the mixture stirred for 30 minutes. Themixture was filtered through a silica gel plug, rinsed with 1/1 ethylacetate/hexane, and the supernatant solution was concentrated underreduced pressure to afford1-(8-tert-butylchroman-4-yl)-3-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)urea.The intermediate was dissolved in tetrahydrofuran (30 mL),tetrabutylammonium fluoride (1.0M in THF, 3.0 mL, 3.0 mmol) was addedand the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure to an oil, chromatographed onsilica gel eluting with 0-to-10% methanol in ethyl acetate, andconcentrate under reduced pressure. The residue was dissolved inmethanol (25 mL), precipitated with water (250 mL), and sonicated. Thesolids were collected by filtration, rinsed with water, and freeze-driedovernight to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.34 (s, 9H), 1.57 (m, 1H), 1.85 (m, 1H), 1.95 (m, 1H), 2.08 (m, 1H),2.27 (dd, 1H), 2.73 (m, 3H), 3.91 (m, 1H), 4.11 (td, 1H), 4.34 (dt, 1H),4.82 (q, 1H), 4.83 (d, 1H), 6.69 (d, 1H), 6.84 (t, 1H), 7.00 (t, 1H),7.14 (m, 3H), 7.43 (s, 1H), 7.74 (d, 1H). MS (ESI) m/z 395.18 (M+H)⁺.Calcd for C₂₄H₃₀N₂O₃.0.29 H₂O: C, 72.11; H, 7.71; N, 7.01. Found: C,72.15; H, 8.03; N, 6.92.

Example 6N-(3,4,7,8,9,10-Hexahydro-2H-benzo[h]chromen-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 6A 5-(Prop-2-ynyloxy)-1,2,3,4-tetrahydronaphthalene

5,6,7,8-Tetrahydronaphthalen-1-ol (Aldrich, 3.93 g, 26.5 mmol),propargyl bromide (80% in toluene, 3.9 ml, 35 mmol), and potassiumcarbonate (4.83 g, 35 mmol) were stirred together in acetonitrile (75mL) for 6 days at ambient temperature. The solvent was removed underreduced pressure, and the residue taken into water and extracted withdiethyl ether. The organic layers were combined, dried with magnesiumsulfate, filtered, and the solvent was evaporated under reduced pressureto afford the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.76 (m,4H), 2.49 (t, J=2.37 Hz, 1H), 2.68 (t, J=5.59 Hz, 2H), 2.75 (t, J=5.59,2H), 4.69 (d, J=2.37 Hz, 2H), 6.74 (dd, J=7.80, 3.73 Hz, 2H), 7.06 (t,J=7.80 Hz, 1H). MS (DCI) m/z 187.06 (M+H)⁺.

Example 6B 5-(3-Chloroprop-2-ynyloxy)-1,2,3,4-tetrahydronaphthalene

Example 6A (5.41 g) was dissolved in acetone (120 mL). Nchlorosuccinimide (4.00 g, 30 mmol) and silver acetate (0.42 g, 2.5mmol) were added, and the mixture was refluxed for 4 hours. Aftercooling, the silver salts were removed by filtration and the filtratewas evaporated under reduced pressure. The residue was taken up indiethyl ether, washed with water and saturated aqueous sodiumbicarbonate, dried with magnesium sulfate, filtered, and concentratedunder reduced pressure to afford a mixture of starting material andproduct. The reaction procedure was repeated with this mixture,affording the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.76 (m,4H), 2.66 (t, J=5.59 Hz, 2H), 2.75 (t, J=5.43, 2H), 4.69 (s, 2H), 6.73(t, J=7.12 Hz, 2H), 7.07 (t, J=7.97 Hz, 1H). MS (DCI) m/z 220.99 (M+H)⁺.

Example 6C 7,8,9,10-Tetrahydro-2H-benzo[h]chromen-4(3H)-one

Example 6B (4.80 g, 21.7 mmol) in ethylene glycol (50 mL) was heated toreflux for 4.5 hours. The mixture was cooled, poured into water, andextracted with diethyl ether. The organic layers were combined, washedwith 1N sodium hydroxide and with saturated ammonium carbonate, anddried with magnesium sulfate. Removal of the solvent under reducedpressure gave a residue which was filtered through a pad of silica geleluting with 1/1 dichloromethane/hexane. The filtrate was evaporatedunder reduced pressure to afford the title compound. ¹H NMR (300 MHz,CDCl₃) δ ppm 1.78 (m, 4H), 2.63 (t, J=5.59 Hz, 2H), 2.76 (t, J=6.44 Hz,4H), 4.53 (t, J=6.44 Hz, 2H), 6.74 (d, J=8.14 Hz, 1H), 7.65 (d, J=8.14Hz, 1H). MS (DCI) m/z 203.07 (M+H)⁺.

Example 6D 7,8,9,10-Tetrahydro-2H-benzo[h]chromen-4(3H)-one O-methyloxime

Example 6C (5.00 g) was dissolved in pyridine (30 mL). Methoxylaminehydrochloride (2.09 g, 25 mmol) was added and the mixture stirred for 16hours at ambient temperature. The pyridine was removed under reducedpressure, and the residue partitioned between water and diethyl ether.The aqueous layer was extracted with diethyl ether, and the combinedorganic layers were washed with 1N sodium hydroxide and 1N hydrochloricacid, dried over magnesium sulfate, filtered and concentrate underreduced pressure. The solvent was removed under reduced pressure toafford the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.76 (m, 4H),2.61 (t, J=5.43 Hz, 2H), 2.72 (t, J=5.43 Hz, 2H), 2.87 (t, J=6.27 Hz,2H), 3.96 (s, 3H), 4.21 (t, J=6.10 Hz, 2H), 6.67 (d, J=8.13 Hz, 1H),7.64 (d, J=8.13 Hz, 1H). MS (DCI) m/z 232.08 (M+H)⁺.

Example 6E 3,4,7,8,9,10-Hexahydro-2H-benzo[h]chromen-4-amine

Example 6D (2.0 g, 8.65 mmol), 10% palladium on carbon (0.2 g), and 20%ammonia in methanol (20 mL) were shaken under hydrogen (60 psi) for 2hours at ambient temperature. The catalyst was removed by filtration andthe solvent was evaporated under reduced pressure to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.75 (m, 4H), 1.83 (m, 1H), 1.93(br s, 2H), 2.13 (m, 1H), 2.59 (t, J=5.09 Hz, 2H), 2.71 (t, J=5.59 Hz,2H), 4.03 (t, J=5.09 Hz, 1H), 4.26 (m, 2H), 6.66 (d, J=7.80 Hz, 1H),7.06 (d, J=7.79 Hz, 1H). MS (DCI) m/z 203.0 (M+NH₄—H₂O)⁺.

Example 6FN-(3,4,7,8,9,10-Hexahydro-2H-benzo[h]chromen-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

To a mixture of di(N-succinimidyl)carbonate (417 mg, 1.63 mmol) inacetonitrile (5 mL) was added Example 1G (430 mg, 1.55 mmol) dissolvedin acetonitrile (5 mL) and pyridine (0.13 mL, 1.63 mmol). After stirringfor 15 minutes at ambient temperature, Example 6E (315 mg, 1.55 mmol) inacetonitrile (5 mL), dimethylformamide (10 mL), anddiisopropylethylamine (0.81 mL, 4.65 mmol) were added and the mixturestirred for minutes. Ethyl acetate (200 mL) and water (200 mL) wereadded and the organic layer was washed with brine, dried over anhydroussodium sulfate, filtered, and concentrate under reduced pressure. Theresidue was chromatographed on silica gel eluting with 0-to-30% ethylacetate in hexane, and concentrated under reduced pressure to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(3,4,7,8,9,10-hexahydro-2H-benzo[h]-chromen-4-yl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL),tetrabutylammonium fluoride (1.0M in THF, 3.1 mL, 3.1 mmol) was added,and the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and chromatographed on silicagel eluting with 0-to-10% methanol in ethyl acetate. The residue wassuspended in methanol (70 mL), sonicated, water (300 mL) was added, andthe sonication was repeated. The solids were collected by filtration,rinsed with water, and freeze-dried to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.58 (m, 1H), 1.67 (m, 4H), 1.88 (m, 2H), 2.04(m, 1H), 2.28 (dd, 1H), 2.73 (m, 5H), 3.91 (m, 1H), 4.13 (td, 1H), 4.29(dt, 1H), 4.76 (q, 1H), 4.84 (d, 1H), 6.61 (d, 1H), 6.69 (d, 1H), 6.99(m, 3H), 7.43 (s, 1H), 7.72 (d, 1H). MS (ESI) m/z 393.21 (M+H)⁺. Calcdfor C₂₄H₂₈N₂O₃.0.20 H₂O: C, 72.78; H, 7.23; N, 7.07. Found: C, 72.79; H,7.29; N, 7.01.

Example 7N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(6-methyl-3,4-dihydro-2H-chromen-4-yl)ureaExample 7A 6-Methylchroman-4-one O-methyl oxime

6-Methylchroman-4-one (Aldrich, 3.24 g, 20 mmol) was dissolved inpyridine (15 mL). Methoxylamine hydrochloride (1.84 g, 22 mmol) wasadded and the mixture stirred for 16 hours at ambient temperature. Thepyridine was removed under reduced pressure, and the residue was addedto water and diethyl ether. The aqueous layer was extracted with diethylether, and the combined organic layers washed with 1N sodium hydroxideand 1N hydrochloric acid and then dried with magnesium sulfate andfiltered. The solvent was removed under reduced pressure to afford thetitle compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 2.28 (s, 3H), 2.88 (t,J=6.27 Hz, 2H), 3.98 (s, 3H), 4.17 (t, J=6.27 Hz, 2H), 6.78 (d, J=8.48Hz, 1H), 7.05 (dd, J=8.48, 2.03 Hz, 1H), 7.70 (d, J=2.03 Hz, 1H). MS(DCI) m/z 192.02 (M+H)⁺.

Example 7B 6-Methyl-chroman-4-ylamine

A solution of Example 7A (4.24 g) in 20% ammonia in methanol (50 mL) wastreated with Raney Nickel, 40 g, under hydrogen (60 psi) for 4 hours atambient temperature. The mixture was filtered, and the solvent wasevaporated under reduced pressure. The residue dissolved in diethylether which was washed sequentially with water and saturated aqueoussodium bicarbonate, dried with magnesium sulfate, filtered andconcentrated under reduced pressure to afford the title compound. H NMR(300 MHz, CDCl₃) δ ppm 1.78-1.88 (m, 1H), 2.10-2.21 (m, 1H), 2.27 (s,3H), 4.01 (m, 1H), 4.22 (m, 2H), 6.71 (d, J=8.5 Hz, 1H), 6.95 (d, J=8.5Hz, 1H), 7.11 (s, 1H). MS (DCI) m/z 164 (M+H)⁺.

Example 7CN-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(6-methyl-3,4-dihydro-2H-chromen-4-yl)urea

Di(N-succinimidyl)carbonate (542 mg, 2.12 mmol) was suspended inacetonitrile (5 mL), and Example 1G (559 mg, 2.02 mmol) dissolved inacetonitrile (5 mL) and pyridine (0.17 mL, 2.12 mmol) was added to themixture. After stirring for 15 minutes at ambient temperature, Example7B (329 mg, 2.02 mmol) dissolved in acetonitrile (5 mL),dimethylformamide (10 mL), and diisopropylethylamine (1.05 mL, 6.05mmol) was added and the mixture stirred for 30 minutes. Ethyl acetate(200 mL) and water (200 mL) were added, and the organic layer was washedwith brine and dried over anhydrous sodium sulfate, filtered,concentrate under reduced pressure. The residue was chromatographed onsilica gel eluting with 0-to-30% ethyl acetate in hexane to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(6-methylchroman-4-yl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL),tetrabutylammonium fluoride (1.0M in THF, 4.0 mL, 4.0 mmol) was added,and the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and chromatographed on silicagel eluting with 0-to-10% methanol in ethyl acetate. The residue wassuspended in methanol (25 mL), sonicated, water was added (250 mL), andthe sonication was repeated. The solids were collected by filtration,rinsed with water, and freeze-dried to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.59 (m, 1H), 1.89 (m, 2H), 2.06 (m, 1H), 2.22(s, 3H), 2.29 (dd, 1H), 2.75 (m, 3H), 3.91 (m, 1H), 4.08 (td, 1H), 4.22(dt, 1H), 4.78 (q, 1H), 4.84 (d, 1H), 6.70 (m, 2H), 7.00 (m, 2H), 7.06(m, 2H), 7.46 (s, 1H), 7.74 (d, 1H). MS (ESI) m/z 353.12 (M+H)⁺. Calcdfor C₂₁H₂₄N₂O₃.0.05 H₂O: C, 71.39; H, 6.87; N, 7.93. Found: C, 71.39; H,6.98; N, 7.90.

Example 8N-[(4R)-3,4-Dihydro-2H-chromen-4-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

Di(N-succinimidyl)carbonate (538 mg, 2.1 mmol) was suspended inacetonitrile (5 mL), Example 1G (555 mg, 2.0 mmol) dissolved inacetonitrile (10 mL) and pyridine (0.17 mL, 2.1 mmol) were added, andthe mixture stirred for 15 minutes at ambient temperature.(R)-chroman-4-amine hydrochloride (J&W PharmLab, 371 mg, 2.0 mmol) anddiisopropylethylamine (1.05 mL, 6.0 mmol) were added and the mixturestirred for 30 minutes. The mixture was filtered through a silica gelplug, rinsed with 1/1 ethyl acetate/hexane, and concentrated underreduced pressure to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-((R)-chroman-4-yl)urea.The intermediate was dissolved in tetrahydrofuran (30 mL),tetrabutylammonium fluoride (1.0M in THF, 4.0 mL, 4.0 mmol) was added,and the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and chromatographed on silicagel eluting with 0-to-10% methanol in ethyl acetate. The residue wassuspended in methanol (20 mL), sonicated after which and water (200 mL)was added. Sonication was repeated and the solids were collected byfiltration, rinsed with water, and freeze-dried to afford the titlecompound. [α]_(D): +46.8° (c1.0, 1:1 DMSO:MeOH). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.58 (m, 1H), 1.86 (m, 1H), 1.97 (m, 1H), 2.09 (m, 1H),2.29 (dd, 1H), 2.75 (m, 3H), 3.91 (m, 1H), 4.13 (td, 1H), 4.27 (m, 1H),4.83 (d, 1H), 4.86 (q, 1H), 6.70 (d, 1H), 6.78 (dd, 1H), 6.90 (td, 1H),7.00 (t, 1H), 7.09 (d, 1H), 7.17 (td, 1H), 7.26 (d, 1H), 7.46 (s, 1H),7.73 (d, 1H). MS (ESI) m/z 339.11 (M+H)⁺. Calcd for C₂₀H₂₂N₂O₃.0.26 H₂O:C, 70.02; H, 6.62; N, 8.17. Found: C, 70.05; H, 6.78; N, 8.13.

Example 9N-[(4S)-3,4-Dihydro-2H-chromen-4-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

Di(N-succinimidyl)carbonate (538 mg, 2.1 mmol) was suspended inacetonitrile (5 mL), and Example 1G (555 mg, 2.0 mmol) dissolved inacetonitrile (10 mL) and pyridine (0.17 mL, 2.1 mmol) was added. Afterstirring for 15 minutes at ambient temperature, (S)-chroman-4-aminehydrochloride (J&W PharmLab, 371 mg, 2.0 mmol) and diisopropylethylamine(1.05 mL, 6.0 mmol) was added and the mixture stirred for 30 minutes.The mixture was filtered through a silica gel plug, rinsed with 1/1ethyl acetate/hexane, and concentrated under reduced pressure to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-((S)-chroman-4-yl)urea.The intermediate was dissolved in tetrahydrofuran (30 mL),tetrabutylammonium fluoride (1.0M in THF, 4.0 mL, 4.0 mmol) was added,and the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and chromatographed on silicagel eluting with 0-to-10% methanol in ethyl acetate. The residue wassuspended in methanol (20 mL), sonicated, and water (200 mL) was added.The sonication was repeated and the solids were collected by filtration,rinsed with water, and freeze-dried to afford the title compound.[α]_(D): −45.0° (c:1.0, 1:1 DMSO:MeOH). ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.58 (m, 1H), 1.86 (m, 1H), 1.97 (m, 1H), 2.09 (m, 1H), 2.29 (dd, 1H),2.75 (m, 3H), 3.91 (m, 1H), 4.13 (td, 1H), 4.27 (m, 1H), 4.83 (d, 1H),4.86 (q, 1H), 6.70 (d, 1H), 6.78 (dd, 1H), 6.90 (td, 1H), 7.00 (t, 1H),7.09 (d, 1H), 7.17 (td, 1H), 7.26 (d, 1H), 7.46 (s, 1H), 7.73 (d, 1H).MS (ESI) m/z 339.06 (M+H)⁺. Calcd for C₂₀H₂₂N₂O₃.0.31 H₂O: C, 69.83; H,6.63; N, 8.14. Found: C, 69.82; H, 6.58; N, 8.13.

Example 10N-(3,4-Dihydro-2H-chromen-2-ylmethyl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 10A Chroman-2-carboxylic acid

4-Oxo-4H-chromene-2-carboxylic acid (Aldrich, 3.0 g, 15.8 mmol) wasadded to a mixture of acetic acid (30 mL) and 10% palladium on carbon(0.3 g) in a Parr shaker. The glass reactor was sealed and flushed withnitrogen, and it was pressurized with hydrogen (60 psi). The mixture wasshaken at 70° C. for 2.5 hours. The mixture was filtered and the solidswere rinsed with methanol. The filtrate was concentrated under reducedpressure and chromatographed on silica gel eluting with 0-to-10%methanol in ethyl acetate to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 2.04 (m, 1H), 2.14 (m, 1H), 2.63 (dt, 1H), 2.78 (dt, 1H),4.76 (dd, 1H), 6.80 (m, 2H), 7.05 (m, 2H). MS (ESI) m/z 177.09 (M−H)⁻.

Example 10B Chroman-2-carboxamide

Example 10A (2.796 g, 15.7 mmol) was dissolved in dichloromethane (60mL), and oxalyl chloride (4.1 mL, 47.1 mmol) was added with a few dropsof dimethylformamide. The mixture stirred for one hour at ambienttemperature and was concentrated under reduced pressure to an orangeoil. The residue was dissolved in dichloromethane (20 mL), and added to0.5M ammonia in dioxane (200 mL). After stirring overnight, andfiltering off the salts, the filtrate was concentrated under reducedpressure and chromatographed on silica gel eluting with 50-to-100% ethylacetate in hexane to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.89 (m, 1H), 2.15 (m, 1H), 2.68 (dt, 1H), 2.80 (ddd,1H), 4.45 (dd, 1H), 6.83 (m, 2H), 7.07 (m, 2H), 7.35 (d, 2H). MS (DCI)m/z 195.08 (M+NH₄)⁺.

Example 10C Chroman-2-ylmethanamine

Lithium aluminum hydride (1.0M in THF, 42.5 mL, 42.5 mmol) was added toExample 10B (2.510 g, 14.2 mmol) dissolved in tetrahydrofuran (40 mL).The mixture was stirred for 1.5 hours at ambient temperature thenrefluxed for two hours. The mixture was chilled to 0° C. followed by thesequential additions of water (3.5 mL), tetrahydrofuran (100 mL), 15%sodium hydroxide (3.5 mL), and water (7.0 mL). The slurry was filtered,the solids were rinsed with ethyl acetate (200 mL), and the filtrate wasconcentrated under reduced pressure to afford the title compound.Obtained 2.329 g of Example 10C. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.55(m, 3H), 2.00 (m, 1H), 2.74 (qd, 4H), 3.87 (dtd, 1H), 6.71 (dd, 1H),6.78 (td, 1H), 7.03 (m, 2H). MS (DCI) m/z 164.07 (M+H)⁺.

Example 10DN-(3,4-Dihydro-2H-chromen-2-ylmethyl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

Di(N-succinimidyl)carbonate (538 mg, 2.1 mmol) was suspended inacetonitrile (5 mL), and Example 1G (555 mg, 2.0 mmol) dissolved inacetonitrile (5 mL) and pyridine (0.17 mL, 2.1 mmol) was added and themixture stirred for 15 minutes at ambient temperature. Example 10C (326mg, 2.0 mmol) dissolved in acetonitrile (10 mL) anddiisopropylethylamine (1.05 mL, 6.0 mmol) was added and the mixturestirred for 30 minutes. The mixture was concentrated under reducedpressure and the residue was chromatographed on silica gel eluting with0-to-40% ethyl acetate in hexane to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(chroman-2-ylmethyl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL),tetrabutylammonium fluoride (1.0M in THF, 4.0 mL, 4.0 mmol) was addedand the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and the residue waschromatographed on silica gel eluting with 0-to-10% methanol in ethylacetate. The residue was suspended in methanol (20 mL), sonicated, water(200 mL) was added, and the sonication was repeated. The solids werecollected by filtration, rinsed with water, and freeze-dried to affordthe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.57 (m, 1H), 1.70(m, 1H), 1.86 (m, 1H), 1.98 (m, 1H), 2.32 (dd, 1H), 2.78 (m, 5H), 3.38(q, 2H), 3.92 (m, 1H), 4.06 (m, 1H), 4.83 (d, 1H), 6.69 (d, 1H), 6.81(m, 3H), 6.98 (t, 1H), 7.07 (m, 2H), 7.65 (t, 2H). MS (ESI) m/z 353.09(M+H)⁺. Calcd for C₂₁H₂₄N₂O₃.0.12 H₂O: C, 71.13; H, 6.89; N, 7.90.Found: C, 71.13; H, 6.63; N, 7.78.

Example 11N-[(7-Ethoxy-3,4-dihydro-2H-chromen-2-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 11A 7-Ethoxy-4-oxo-4H-chromene-2-carboxylic acid

To a solution of 1-(4-ethoxy-2-hydroxyphenyl)ethanone (Aldrich, 5.0 g,27.7 mmol) and diethyl oxalate (8.3 mL, 61 mmol) in ethanol (50 mL) wasadded sodium ethoxide (21% in EtOH, 31 mL, 83 mmol) and the mixture wasrefluxed for 1.5 hours. The mixture was cooled to ambient temperature,diethyl ether (150 mL), water (150 mL) and 12N hydrochloric acid (7 mL)were added. The separated organic layer was washed with brine, driedover anhydrous sodium sulfate, filtered and was concentrated underreduced pressure to afford ethyl7-ethoxy-4-oxo-4H-chromene-2-carboxylate. The intermediate was dissolvedin acetic acid (70 mL) and 12N hydrochloric acid (8.5 mL), heated toreflux for 2 hours, and cooled to ambient temperature. Water (300 mL)was added and the solids were collected by filtration, rinsed withwater, and freeze-dried to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.38 (t, 3H), 4.20 (q, 2H), 6.84 (s, 1H), 7.08 (dd, 1H),7.19 (d, 1H), 7.92 (d, 1H). MS (APCI) m/z 235.04 (M+H)⁺.

Example 11B 7-Ethoxychroman-2-carboxylic acid

Example 11A (3.0 g, 12.8 mmol) was added to a mixture of acetic acid (30mL) and 10% palladium on carbon (0.3 g) in a Parr shaker. The glassreactor was sealed and flushed with nitrogen, and pressurized withhydrogen (60 psi). The mixture was shaken at 70° C. for 3 hours. Themixture was filtered and the solids were rinsed with methanol. Thefiltrate was concentrated under reduced pressure and chromatographed onsilica gel eluting with 0-to-10% methanol in ethyl acetate to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.29 (t, 3H), 2.01 (m,1H), 2.10 (m, 1H), 2.57 (m, 1H), 2.69 (dt, 1H), 3.94 (q, 2H), 4.73 (dd,1H), 6.34 (d, 1H), 6.40 (dd, 1H), 6.90 (d, 1H), 12.94 (br s, 1H). MS(ESI) m/z 221.12 (M−H)⁻.

Example 11C 7-Ethoxychroman-2-carboxamide

Example 11B (2.462 g, 11.1 mmol) was dissolved in dichloromethane (40mL) followed by the addition of oxalyl chloride (2.9 mL, 33.2 mmol) anda few drops of dimethylformamide. The mixture stirred for one hour atambient temperature, was concentrate under reduced pressure, anddissolved in dichloromethane (20 mL), and added to 0.5M ammonia indioxane (200 mL). The mixture stirred overnight and was filtered. Thefiltrate was concentrate under reduced pressure, and the residue waschromatographed on silica gel eluting with 50-to-100% ethyl acetate inhexane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.29 (t, 3H), 1.86 (m, 1H), 2.12 (m, 1H), 2.59 (dt, 1H), 2.70 (ddd, 1H),3.94 (q, 2H), 4.42 (dd, 1H), 6.41 (m, 2H), 6.92 (d, 1H), 7.33 (d, 2H).MS (DCI) m/z 239.13 (M+NH₄)¹.

Example 11D (7-Ethoxychroman-2-yl)methanamine

Lithium aluminum hydride (1.0M in THF, 24.3 mL, 24.3 mmol) was added toExample 11C (1.79 g, 8.09 mmol) suspended in tetrahydrofuran (60 mL).The mixture stirred for 1.5 hours at ambient temperature and wasrefluxed for two hours. The mixture was chilled to 0° C., and wassequentially added water (2.0 mL), tetrahydrofuran (60 mL), 15% sodiumhydroxide (2.0 mL), and water (4.0 mL). The mixture was filtered, thesolids were rinsed with ethyl acetate (200 mL), and the filtrate wasconcentrated under reduced pressure to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.28 (t, 3H), 1.56 (m, 3H), 1.98 (m, 1H), 2.70(m, 4H), 3.84 (m, 1H), 3.92 (q, 2H), 6.28 (d, 1H), 6.36 (dd, 1H), 6.90(d, 1H). MS (DCI) m/z 208.10 (M+H)⁺.

Example 11EN-[(7-Ethoxy-3,4-dihydro-2H-chromen-2-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

Di(N-succinimidyl)carbonate (538 mg, 2.1 mmol) was suspended inacetonitrile (5 mL) followed by the addition of Example 1G (555 mg, 2.0mmol) dissolved in acetonitrile (5 mL) and pyridine (0.17 mL, 2.1 mmol)and the mixture stirred for 15 minutes at ambient temperature. Example11D (415 mg, 2.0 mmol) dissolved in acetonitrile (10 mL) anddiisopropylethylamine (1.05 mL, 6.0 mmol) was added and the mixturestirred for 30 minutes. The mixture was concentrated under reducedpressure and the residue was chromatographed on silica gel eluting with0-to-40% ethyl acetate in hexane to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-((7-ethoxychroman-2-yl)methyl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL), andtetrabutylammonium fluoride (1.0M in THF, 4.0 mL, 4.0 mmol) was addedand the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and the residue waschromatographed on silica gel eluting with 0-to-10% methanol in ethylacetate. The solid was suspended in methanol (20 mL), sonicated, andwater (200 mL) was added. The sonication was repeated and the solidswere collected by filtration, rinsed with water, and freeze-dried toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.29 (t, 3H),1.61 (m, 2H), 1.86 (m, 1H), 1.95 (m, 1H), 2.32 (dd, 1H), 2.74 (m, 5H),3.37 (q, 2H), 3.92 (m, 1H), 3.93 (q, 2H), 4.04 (m, 1H), 4.84 (d, 1H),6.32 (d, 1H), 6.39 (dd, 1H), 6.69 (d, 1H), 6.84 (t, 1H), 6.93 (d, 1H),6.98 (t, 1H), 7.65 (m, 2H). MS (ESI) m/z 397.19 (M+H)⁺. Calcd forC₂₃H₂₈N₂O₄.0.15 H₂O: C, 69.20; H, 7.15; N, 7.02. Found: C, 69.26; H,7.00; N, 6.43.

Example 12N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[(6-methyl-3,4-dihydro-2H-chromen-2-yl)methyl]ureaExample 12A 6-Methylchroman-2-carboxylic acid

6-Methyl-4-oxo-4H-chromene-2-carboxylic acid (Aldrich, 3.5 g, 17.1 mmol)was added to a mixture of acetic acid (50 mL) and 10% palladium oncarbon (0.35 g) in a Parr shaker. The glass reactor was sealed andflushed with nitrogen, and pressurized with hydrogen (60 psi). Themixture was shaken at 70° C. for 2.5 hours, and filtered and solids wererinsed with methanol. The filtrate was concentrated under reducedpressure to afford the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm2.09-2.23 (m, 1H), 2.25 (s, 3H), 2.28-2.40 (m, 1H), 2.72-2.86 (m, 2H),4.71 (dd, J=8.48, 3.39 Hz, 1H), 6.83 (t, J=8.65 Hz, 2H), 6.90-6.96 (m,1H). MS (ESI) m/z 210.1 (M+NH₄)⁺.

Example 12B 6-Methylchroman-2-carboxamide

To a solution of Example 12A (3.3 g, 17.1 mmol) dissolved indichloromethane (60 mL) was added oxalyl chloride (4.5 mL, 51.6 mmol)and a few drops of dimethylformamide. After stirring for 30 minutes atambient temperature, the solvent was evaporated and the residue wasdissolved in dichloromethane (30 mL) and added to 0.5M ammonia indioxane (100 mL). The mixture stirred overnight, was filtered, and thefiltrate was concentrate under reduced pressure. The residue wasdissolved in ethyl acetate, and filtered through a silica gel plug andthe filtrate was concentrated under reduced pressure to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.79-1.94 (m, 1H), 2.07-2.17(m, 1H), 2.19 (s, 3H), 2.62 (dt, J=16.53, 5.30 Hz, 1H), 2.70-2.82 (m,1H), 4.41 (dd, J=8.99, 3.22 Hz, 1H), 6.73 (d, J=8.14 Hz, 1H), 6.84-6.91(m, 2H), 7.35 (d, J=6.10 Hz, 2H). MS (ESI) m/z 192.13 (M+H)⁺.

Example 12C (6-Methylchroman-2-yl)methanamine

Lithium aluminum hydride (1.0M in THF, 31.5 mL, 31.5 mmol) was added toExample 12B (2.009 g, 10.5 mmol) dissolved in tetrahydrofuran (40 mL).The mixture stirred for 1.5 hours at ambient temperature, and thenrefluxed for 2.5 hours. After cooling to 0° C., the following was addedsequentially:water (2.6 mL), tetrahydrofuran (75 mL), 15% sodiumhydroxide (2.6 mL), and water (5.2 mL). The slurry was filtered, thesolids were rinsed with ethyl acetate (200 mL), and the filtrate wasconcentrated under reduced pressure to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.55 (m, 3H), 1.98 (m, 1H), 2.17 (s, 3H), 2.71(qd, 4H), 3.81 (dtd, 1H), 6.59 (d, 1H), 6.84 (m, 2H). MS (DCI) m/z178.10 (M+H)⁺.

Example 12DN-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[(6-methyl-3,4-dihydro-2H-chromen-2-yl)methyl]urea

Di-(N-succinimidyl)carbonate (538 mg, 2.1 mmol) was suspended inacetonitrile (5 mL) after which Example 1G (555 mg, 2.0 mmol) dissolvedin acetonitrile (5 mL) and pyridine (0.17 mL, 2.1 mmol) were added.After stirring for 15 minutes at ambient temperature, Example 12C (354mg, 2.0 mmol) dissolved in acetonitrile (10 mL) anddiisopropylethylamine (1.05 mL, 6.0 mmol) were added and the mixturestirred for 30 minutes. The mixture was concentrated under reducedpressure and chromatographed on silica gel eluting with 0-to-40% ethylacetate in hexane, to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-((6-methylchroman-2-yl)methyl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL), andtetrabutylammonium fluoride (1.0M in THF, 4.0 mL, 4.0 mmol) was addedand the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and chromatographed on silicagel eluting with 0-to-10% methanol in ethyl acetate. The residue wassuspended in methanol (20 mL), sonicated, and water (200 mL) was added.The sonication was repeated and the solids were collected by filtration,rinsed with water, and freeze-dried to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.62 (m, 2H), 1.86 (m, 1H), 1.96 (m, 1H), 2.19(s, 3H), 2.32 (dd, 1H), 2.76 (m, 5H), 3.36 (q, 2H), 3.92 (m, 1H), 4.02(m, 1H), 4.83 (d, 1H), 6.68 (m, 2H), 6.86 (m, 3H), 6.98 (t, 1H), 7.64(t, 2H). MS (ESI) m/z 367.17 (M+H)⁺. Calcd for C₂₂H₂₆N₂O₃.0.11 H₂O: C,71.72; H, 7.17; N, 7.60. Found: C, 71.71; H, 7.02; N, 7.50.

Example 13N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[(8-isopropyl-3,4-dihydro-2H-chromen-2-yl)methyl]ureaExample 13A 1-(2-Hydroxy-3-isopropylphenyl)ethanone

2-Hydroxy-3-isopropylbenzoic acid (Aldrich, 4.0 g, 22.2 mmol) wasdissolved in tetrahydrofuran (20 mL), chilled to −75° C., andmethyllithium (1.6M in diethyl ether, 42 mL, 66.6 mmol) was added. Themixture stirred overnight at ambient temperature. The mixture wasquenched with methanol (50 mL), concentrate under reduced pressure, andethyl acetate (200 mL) was added. The mixture was washed with 1Nhydrochloric acid (200 mL), water (200 mL), and brine and the organiclayer was dried over anhydrous sodium sulfate, filtered and concentrateunder reduced pressure. The residue was chromatographed on silica geleluting with 0-to-30% ethyl acetate in hexane to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.23 (d, 6H), 2.64 (s, 3H), 3.39(m, 1H), 6.87 (t, 1H), 7.41 (dd, 1H), 7.59 (dd, 1H), 12.69 (s, 1H). MS(DCI) m/z 179.07 (M+H)⁺.

Example 13B 8-Isopropyl-4-oxo-4H-chromene-2-carboxylic acid

To a solution of Example 13A (2.048 g, 11.5 mmol) in ethanol (60 mL) wasadded diethyl oxalate (3.43 mL, 25.3 mmol) and sodium ethoxide (21% inEtOH, 12.9 mL, 34.5 mmol) and the mixture was refluxed for 30 minutes.The mixture was cooled to ambient temperature, partitioned betweendiethyl ether (150 mL) and water (150 mL). Hydrochloric acid (12N, 3 mL)was added and the separated organic layer was washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford ethyl 8-isopropyl-4-oxo-4H-chromene-2-carboxylate.After dissolving the intermediate in acetic acid (45 mL) and 12Nhydrochloric acid (7.5 mL), the mixture was heated to reflux for 5.5hours then cooled to ambient temperature. Water (400 mL) was added andthe mixture was extracted with ethyl acetate (400 mL). The combinedorganic layers were washed with water (400 mL) and brine, dried overanhydrous sodium sulfate and filtered. The solution was concentratedunder reduced pressure and vacuum dried overnight to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.32 (d, 6H), 3.56 (m, 1H),6.91 (s, 1H), 7.48 (t, 1H), 7.78 (dd, 1H), 7.89 (dd, 1H). MS (ESI) m/z232.94 (M+H)⁺.

Example 13C 8-Isopropylchroman-2-carboxylic acid

Example 13B (2.421 g, 10.4 mmol) was added to a mixture of acetic acid(30 mL) and 10% palladium on carbon (0.25 g) in a Parr shaker. The glassreactor was sealed and flushed with nitrogen, and pressurized withhydrogen (60 psi). The mixture was shaken at 70° C. for 3 hours. Themixture was filtered, the solids were rinsed with methanol and thefiltrate was concentrated under reduced pressure and chromatographed onsilica gel cluting with 0-to-50% ethyl acetate in hexane to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.16 (dd, 6H), 2.09 (m,2H), 2.63 (m, 1H), 2.76 (dt, 1H), 3.22 (m, 1H), 4.81 (dd, 1H), 6.77 (t,1H), 6.85 (dd, 1H), 6.99 (dd, 1H), 12.90 (br s, 1H). MS (ESI) m/z 219.15(M−H)⁻.

Example 13D 8-Isopropylchroman-2-carboxamide

To a solution of Example 13C (2.157 g, 9.79 mmol) in dichloromethane (40mL) was added oxalyl chloride (2.56 mL, 29.4 mmol) and a few drops ofdimethylformamide. After stirring for one hour at ambient temperature,the mixture was concentrate under reduced pressure, dissolved indichloromethane (20 mL), and added to 0.5M ammonia in dioxane (200 mL).After stirring overnight, the mixture was filtered, the filtrate wasconcentrate under reduced pressure, and the residue was chromatographedon silica gel eluting with 0-to-50% ethyl acetate in hexane to affordthe title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.24 (dd, 6H), 2.06(m, 1H), 2.43 (m, 1H), 2.87 (m, 2H), 3.28 (m, 1H), 4.54 (dd, 1H), 5.53(s, 1H), 6.55 (s, 1H), 6.91 (m, 2H), 7.07 (dd, 1H). MS (DCI) m/z 237.11(M+NH₄)⁺.

Example 13E (8-Isopropylchroman-2-yl)methanamine

Lithium aluminum hydride (1.0M in THF, 19.6 mL, 19.6 mmol) was added toExample 13D (1.435 g, 6.54 mmol) dissolved in tetrahydrofuran (30 mL).The mixture stirred for 1.5 hours at ambient temperature, and refluxedfor 2 hours. After cooling to 0° C., the following was addedsequentially: water (1.6 mL), tetrahydrofuran (50 mL), 15% sodiumhydroxide (1.6 mL) and additional water (3.2 mL). The mixture wasfiltered, and the solids were rinsed with ethyl acetate (200 mL). Thecombined filtrates were concentrated under reduced pressure to affordthe title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.21 (dd, 6H), 1.64(br s, 2H), 1.76 (m, 1H), 1.94 (m, 1H), 2.78 (ddd, 1H), 2.88 (m, 1H),2.95 (d, 2H), 3.28 (m, 1H), 3.97 (m, 1H), 6.81 (t, 1H), 6.89 (d, 1H),7.02 (dd, 1H). MS (DCI) m/z 206.11 (M+H)⁺.

Example 13FN-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[(8-isopropyl-3,4-dihydro-2H-chromen-2-yl)methyl]urea

Di(N-succinimidyl)carbonate (538 mg, 2.1 mmol) was suspended inacetonitrile (5 mL) followed by the addition of Example 1G (555 mg, 2.0mmol) dissolved in acetonitrile (5 mL) and pyridine (0.17 mL, 2.1 mmol).The mixture was stirred for 15 minutes at ambient temperature afterwhich Example 13E (411 mg, 2.0 mmol) dissolved in acetonitrile (10 mL)and diisopropylethylamine (1.05 mL, 6.0 mmol) were added and the mixturestirred for 30 minutes. The mixture was concentrated under reducedpressure and chromatographed on silica gel eluting with 0-to-40% ethylacetate in hexane to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-((8-isopropylchroman-2-yl)methyl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL),tetrabutylammonium fluoride (1.0M in THF, 4.0 mL, 4.0 mmol) was addedand the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and chromatographed on silicagel eluting with 0-to-10% methanol in ethyl acetate. The residue wasdissolved in ethyl acetate (200 mL), washed with 1N sodium hydroxide(200 mL), water (200 mL), and brine and the combined organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 1.14 (d, 6H), 1.62 (m, 2H), 1.86 (m, 1H), 1.97 (m, 1H), 2.32 (dd,1H), 2.78 (m, 5H), 3.25 (m, 1H), 3.41 (t, 2H), 3.92 (m, 1H), 4.06 (m,1H), 4.85 (d, 1H), 6.76 (m, 3H), 6.87 (dd, 1H), 6.98 (m, 2H), 7.61 (d,1H), 7.66 (s, 1H). MS (ESI) m/z 395.24 (M+H)⁺. Calcd for C₂₄H₃₀N₂O₃.0.27EtOAc: C, 72.01; H, 7.75; N, 6.70. Found: C, 71.96; H, 7.85; N, 6.81.

Example 14N-(8-tert-Butyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 14A 3-Bromo-N-(2-tert-butylphenyl)propanamide

2-tert-butylaniline (Aldrich, 24.7 g, 166 mmol) was dissolved indichloromethane (100 mL) and potassium carbonate (47.0 g, 340 mmol) wasadded. 3-Bromopropionyl chloride (29.1 g, 170 mmol) in dichloromethane(50 mL) was added dropwise and the mixture stirred for 3 hours atambient temperature. Water was added slowly to quench the mixture, andthe organic layer was separated and washed twice with water, dried withmagnesium sulfate, filtered, and concentrated under reduced pressure toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.32 (s, 9H),2.97 (t, J=6.44 Hz, 2H), 3.74 (t, J=6.27 Hz, 2H), 7.00-7.06 (m, 1H),7.16-7.25 (m, 2H), 7.36-7.42 (m, 1H), 9.35 (s, 1H). MS (DCI) m/z 284.0(M+H)⁺.

Example 14B 1-(2-tert-Butylphenyl)azetidin-2-one

Sodium tert-butoxide (2.5 g, 26 mmol) was dissolved in dimethylformamide(100 mL) followed by the addition of Example 14A (7.1 g, 25 mmol)dissolved in dimethylformamide (10 mL) and the mixture stirred for 2hours at ambient temperature. Ethyl acetate (200 mL) was added and theorganic layer was washed three times with water, dried with magnesiumsulfate, filtered, and concentrated under reduced pressure to afford thetitle compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.41 (s, 9H), 3.10 (t,J=4.41 Hz, 2H), 3.64 (t, J=4.41 Hz, 2H), 7.13 (dd, J=7.46, 2.03 Hz, 1H),7.19-7.31 (m, 2H), 7.46 (dd, J=7.80, 1.70 Hz, 1H). MS (DCI) m/z 204.0(M+H)⁺.

Example 14C 8-tert-Butyl-2,3-dihydroquinolin-4(1H)-one

Example 14B (4.7 g, 23 mmol) was dissolved in dichloroethane (500 mL)followed by the addition of trifluoromethanesulfonic acid (10 g, 66.6mmol) and the mixture stirred for 18 hours at ambient temperature. Themixture was quenched with potassium carbonate (20 g) and water (1 mL),stirred for 2 hours, and filtered through a plug of magnesium sulfateand concentrated under reduced pressure to afford the title compound. ¹HNMR (300 MHz, CDCl₃) δ ppm 1.43 (s, 9H), 2.64-2.74 (m, 2H), 3.56-3.66(m, 2H), 6.70 (t, J=7.80 Hz, 1H), 7.37 (dd, J=7.46, 1.70 Hz, 1H), 7.83(dd, J=7.97, 1.53 Hz, 1H). MS (DCI) m/z 204.0 (M+H)⁺.

Example 14D 8-tert-Butyl-1-methyl-2,3-dihydroquinolin-4(1H)-one

Paraformaldehyde (5.0 g, 167 mmol) and 3 drops of glacial acetic acidwere added to Example 14C (4.7 g, 23 mmol) in dichloroethane (50 mL) andthe mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (24g, 113 mmol) was added and the mixture was heated to 60° C. for 4 hours.After cooling, ethyl acetate (300 mL) was added, and the organic layerwas washed with 10% sodium bicarbonate, 5% citric acid, brine. Thesolution was dried over magnesium sulfate, filtered and concentratedunder reduced pressure to afford the title compound. ¹H NMR (300 MHz,CDCl₃) δ ppm 1.48 (s, 9H), 2.72 (s, 3H), 2.83 (t, J=6.27 Hz, 2H), 3.47(t, J=6.44 Hz, 2H), 7.17 (t, J=7.80 Hz, 1H), 7.59 (dd, J=7.97, 1.53 Hz,1H), 7.86 (dd, J=7.46, 1.70 Hz, 1H). MS (DCI) m/z 218.1 (M+H)⁺.

Example 14E 8-tert-Butyl-1-methyl-2,3-dihydroquinolin-4(1H)-one O-methyloxime

Methoxylamine hydrochloride (0.86 g, 10.3 mmol) was added to a solutionof Example 14D (2.04 g, 9.39 mmol) in pyridine (20 mL) and the mixturestirred overnight at ambient temperature. The mixture was concentratedunder reduced pressure and ethyl acetate (200 mL) was added. Thesolution was washed twice with water (200 mL), once with brine, driedover anhydrous sodium sulfate, filtered, and concentrate under reducedpressure. The residue was chromatographed on silica gel eluting with0-to-25% ethyl acetate in hexane to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.41 (s, 9H), 2.46 (s, 3H), 2.80 (m, 2H), 3.07(m, 2H), 3.93 (s, 3H), 7.11 (t, J=7.80 Hz, 1H), 7.35 (dd, J=7.97, 1.53Hz, 1H), 7.62 (dd, J=7.63, 1.53 Hz, 1H). MS (DCI) m/z 247.14 (M+H)⁺.

Example 14F 8-tert-Butyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-amine

Example 14E (1.227 g, 4.98 mmol) and Raney nickel (11.9 g) were added toa mixture of 20% ammonia in methanol (22 mL) in a Parr shaker. The glassreactor was sealed and flushed with nitrogen and pressurized withhydrogen (60 psi). The mixture was shaken at ambient temperature for onehour. The solids were filtered off and washed with methanol and thefiltrate was concentrated under reduced pressure to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.39 (s, 9H), 1.83 (m, 1H),2.30 (m, 1H), 2.57 (s, 3H), 2.98 (t, J=6.61 Hz, 2H), 3.95 (t, J=7.29 Hz,1H), 6.99 (t, J=7.63 Hz, 1H), 7.18 (d, J=8.14 Hz, 1H), 7.33 (d, J=7.46Hz, 1H). MS (DCI) m/z 219.1 (M+H)⁺.

Example 14GN-(8-tert-Butyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

To a mixture of di(N-succinimidyl)carbonate (538 mg, 2.1 mmol) suspendedin acetonitrile (5 mL) was added Example 1G (555 mg, 2.0 mmol) dissolvedin acetonitrile (5 mL) and pyridine (0.17 mL, 2.1 mmol). The mixturestirred for 15 minutes at ambient temperature and Example 14F (437 mg,2.0 mmol), dissolved in acetonitrile (10 mL) and diisopropylethylamine(1.05 mL, 6.0 mmol), was added and the mixture stirred for 30 minutes atambient temperature. The mixture was concentrated under reduced pressureand chromatographed on silica gel eluting with 0-to-30% ethyl acetate inhexane, to afford1-(8-tert-butyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-3-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)urea.The intermediate was dissolved in tetrahydrofuran (25 mL), andtetrabutylammonium fluoride (1.0M in THF, 4.0 mL, 4.0 mmol) was added,and the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and chromatographed on silicagel eluting with 0-to-10% methanol in ethyl acetate. The residue wasdissolved in ethyl acetate (250 mL), washed with 1.0N sodium hydroxide(250 mL), water (250 mL), and brine, and dried over anhydrous sodiumsulfate, filtered, concentrate under reduced pressure, and vacuum driedovernight to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.42 (s, 9H), 1.59 (m, 1H), 1.70 (m, 1H), 1.87 (m, 1H), 2.37 (m, 2H),2.62 (s, 3H), 2.77 (m, 3H), 3.04 (m, 2H), 3.91 (m, 1H), 4.84 (d, J=4.41Hz, 1H), 4.95 (q, J=7.46 Hz, 1H), 6.70 (d, J=7.46 Hz, 1H), 7.01 (m, 3H),7.14 (d, J=7.46 Hz, 1H), 7.26 (dd, J=7.97, 1.53 Hz, 1H), 7.51 (s, 1H),7.74 (d, J=8.14 Hz, 1H). MS (ESI) m/z 408.27 (M+H)⁺. Calcd forC₂₅H₃₃N₃O₂.0.29 EtOAc: C, 72.55; H, 8.22; N, 9.70. Found: C, 72.54; H,8.53; N, 9.73.

Example 15N-(1-Benzyl-1,2,3,4-tetrahydroquinolin-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 15A 3-(Phenylamino)propanoic acid

Aniline (9.11 mL, 100 mmol) was dissolved in acetonitrile (100 mL) andheated to reflux while (3-propiolactone (Sigma, 6.29 mL, 100 mmol) inacetonitrile (20 mL) was added dropwise for 30 minutes. The mixture wasrefluxed for 3 hours and then stirred overnight at ambient temperature.The mixture was concentrate under reduced pressure, and chromatographedon silica gel eluting with 40-to-100% ethyl acetate in hexane to affordthe title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 2.69 (t, J=6.27 Hz,2H), 3.48 (t, J=6.44 Hz, 2H), 6.66 (dd, J=8.81, 1.02 Hz, 2H), 6.75 (t,J=7.46 Hz, 1H), 7.20 (dd, J=8.65, 7.29 Hz, 2H). MS (DCI) m/z 166.05(M+H)⁺.

Example 15B 2,3-Dihydroquinolin-4(1H)-one

Example 15A (10.34 g, 62.6 mmol) and Eaton's reagent (Aldrich, 185 mL,7.7% P₂O₅ in CH₃SO₃H) were heated at 95° C. for 17 hours, and thenstirred overnight at ambient temperature. The mixture was added to ice(1 L) with stirring, and 200 mL, 1N sodium hydroxide in 25 mL portionswas added to adjust the pH to 10. The mixture was extracted twice withethyl acetate (1 L). The combined organic solution was washed withbrine, dried over sodium sulfate, filtered, and concentrate underreduced pressure. The residue was chromatographed on silica gel elutingwith 30-70% ethyl acetate in hexane to afford the title compound. ¹H NMR(300 MHz, CDCl₃) δ ppm 2.71 (t, J=6.96 Hz, 2H), 3.50 (t, J=6.96 Hz, 2H),4.37 (br s, 1H), 6.67 (d, J=7.80 Hz, 1H), 6.74 (t, J=7.46 Hz, 1H), 7.30(td, J=7.71, 1.53 Hz, 1H), 7.85 (dd, J=7.80, 1.70 Hz, 1H). MS (DCI) m/z148.02 (M+H)⁺.

Example 15C 1-Benzyl-2,3-dihydroquinolin-4(1H)-one

Example 15B (1.32 g, 9.0 mmol), benzyl bromide (1.12 mL, 9.45 mmol) anddiisopropylethylamine (3.14 mL, 18.0 mmol) in acetonitrile (12 mL) wereheated on a microwave at 150° C. for 30 minutes. Ethyl acetate (200 mL)was added and the organic layer was washed twice with water (200 mL) andbrine, dried over sodium sulfate, filtered, concentrate under reducedpressure, and chromatographed on silica gel eluting with 0-to-40% ethylacetate in hexane to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 2.68 (t, J=7.12 Hz, 2H), 3.63 (t, J=6.95 Hz, 2H), 4.64(s, 2H), 6.66 (t, J=6.95 Hz, 1H), 6.78 (d, J=8.82 Hz, 1H), 7.31 (m, 6H),7.70 (dd, J=7.80, 1.70 Hz, 1H). MS (DCI) m/z 238.09 (M+H)⁺.

Example 15D 1-Benzyl-2,3-dihydroquinolin-4(1H)-one O-methyl oxime

Methoxylamine hydrochloride (0.74 g, 8.9 mmol) was added to a solutionof Example 15C (1.92 g, 8.1 mmol) in pyridine (20 mL) and stirredovernight at ambient temperature. The mixture was concentrate underreduced pressure, ethyl acetate (200 mL) was added, and the organiclayer was washed twice with water (200 mL) and brine, dried over sodiumsulfate, filtered, and concentrate under reduced pressure. The residuewas chromatographed on silica gel eluting with 0-20% ethyl acetate inhexane to afford the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 2.88(t, J=6.44 Hz, 2H), 3.29 (t, J=6.44 Hz, 2H), 3.97 (s, 3H), 4.47 (s, 2H),6.65 (d, J=8.14 Hz, 1H), 6.70 (t, J=7.46 Hz, 1H), 7.13 (td, J=7.80, 1.70Hz, 1H), 7.31 (m, 5H), 7.92 (dd, J=7.80, 1.70 Hz, 1H). MS (DCI) m/z267.11 (M+H)⁺.

Example 15E 1-Benzyl-1,2,3,4-tetrahydroquinolin-4-amine

Example 15D (2.11 g, 7.92 mmol) was added to a mixture of 20% ammonia inmethanol (80 mL) and Raney nickel (20 g) in a Parr shaker. The glassreactor was sealed and flushed with nitrogen, and pressurized withhydrogen (60 psi). The mixture was shaken at ambient temperature for 4hours. The solids were filtered off and washed with methanol, and thefiltrate was concentrated under reduced pressure to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.48 (br s, 2H), 1.88 (m, 1H),2.10 (m, 1H), 3.34 (m, 1H), 3.52 (td, J=10.94, 3.56 Hz, 1H), 4.05 (br s,1H), 4.51 (s, 2H), 6.53 (d, J=8.48 Hz, 1H), 6.64 (t, J=7.29 Hz, 1H),7.03 (m, 1H), 7.27 (m, 6H). MS (DCI) m/z 239.1 (M+H)⁺.

Example 15FN-(1-Benzyl-1,2,3,4-tetrahydroquinolin-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

Di(N-succinimidyl)carbonate (538 mg, 2.1 mmol) was suspended inacetonitrile (5 mL) followed by the addition of Example 1G (555 mg, 2.0mmol) dissolved in acetonitrile (5 mL) and pyridine (0.17 mL, 2.1 mmol).The mixture was stirred for 15 minutes at ambient temperature andExample 15E (477 mg, 2.0 mmol) dissolved in acetonitrile (10 mL) anddiisopropylethylamine (1.05 mL, 6.0 mmol) were added and the mixturestirred for 30 minutes. The mixture was concentrated under reducedpressure and chromatographed on silica gel eluting with 0-30% ethylacetate in hexane, to afford1-(1-benzyl-1,2,3,4-tetrahydroquinolin-4-yl)-3-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL),tetrabutylammonium fluoride (1.0M in THF, 4.0 mL, 4.0 mmol) was added,and the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and chromatographed on silicagel eluting with 0-10% methanol in ethyl acetate. The residue wassuspended in methanol (30 mL), sonicated after which water (300 mL) wasadded. The sonication was repeated, and the solids were collected byfiltration, rinsed with water, and freeze-dried overnight to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.57 (m, 1H), 1.86 (m,1H), 2.00 (m, 2H), 2.31 (m, 1H), 2.75 (m, 3H), 3.42 (m, 2H), 3.91 (m,1H), 4.54 (d, J=4.07 Hz, 2H), 4.79 (m, 1H), 4.84 (d, J=4.07 Hz, 1H),6.53 (d, J=8.13 Hz, 1H), 6.55 (t, J=7.29 Hz, 1H), 6.69 (d, J=7.46 Hz,1H), 6.99 (m, 3H), 7.13 (d, J=7.12 Hz, 1H), 7.29 (m, 5H), 7.49 (s, 1H),7.77 (dd, J=7.63, 3.22 Hz, 1H). MS (ESI) m/z 428.2 (M+H)⁺. Calcd forC₂₇H₂₉N₃O₂.0.42 H₂O: C, 74.53; H, 6.91; N, 9.66. Found: C, 74.56; H,7.06; N, 9.60.

Example 16N-[1-Benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 16A 3-Bromo-N-(3-(trifluoromethyl)phenyl)propanamide

3-(Trifluoromethyl)aniline (Aldrich, 16.11 g, 100 mmol) was added to asuspension of potassium carbonate (27.64 g, 200 mmol) in dichloromethane(225 mL) followed by the addition of 3-bromopropionyl chloride (10.08mL, 100 mmol) in dichloromethane (40 mL). The mixture was stirred for 4hours at ambient temperature, quenched with water (200 mL), the organiclayer was washed twice with water (200 mL), dried over sodium sulfate,filtered through a silica gel plug, and rinsed with 1:1 ethylacetate:hexane (400 mL), and concentrated under reduced pressure toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.99 (t,J=6.27 Hz, 2H), 3.74 (t, J=6.44 Hz, 2H), 7.41 (d, J=7.80 Hz, 1H), 7.56(t, J=7.97 Hz, 1H), 7.77 (d, J=8.48 Hz, 1H), 8.11 (s, 1H), 10.39 (s,1H). MS (DCI) m/z 312.99 (M+NH₄)⁺.

Example 16B 1-(3-(Trifluoromethyl)phenyl)azetidin-2-one

Sodium tert-butoxide (9.58 g, 100 mmol) was suspended indimethylformamide (300 mL) and stirred for an hour at ambienttemperature. Example 16A (30.13 g, 102 mmol) in dimethylformamide (50mL) was added and the mixture stirred for 2.5 hours. The mixture waspartitioned between tert-butyl methyl ether (1.0 L) and water (1.0 L),and the organic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.13 (t, J=4.58 Hz, 2H), 3.71(t, J=4.58 Hz, 2H), 7.44 (m, 1H), 7.60 (m, 2H), 7.67 (s, 1H). MS (DCI)m/z 233.05 (M+NH₄)⁺.

Example 16C 7-(Trifluoromethyl)-2,3-dihydroquinolin-4(1H)-one and5-(Trifluoromethyl)-2,3-dihydroquinolin-4(1H)-one

To a solution of Example 16B (10.75 g, 50 mmol) dissolved indichloroethane (500 mL) was added trifluoromethanesulfonic acid (15.0 g,100 mmol), and the mixture was stirred at 75° C. for 4 hours. Aftercooling potassium carbonate (50 g) and water (500 mL) were added. Theorganic layer was washed with water (500 mL) and brine, and dried oversodium sulfate, concentrated under reduced pressure to afford the titlecompound as a mixture of regioisomers: ˜45%7-(trifluoromethyl)-2,3-dihydroquinolin-4(1H)-one and ˜55%5-(trifluoromethyl)-2,3-dihydroquinolin-4(1H)-one. MS (DCI) m/z 233.07(M+NH₄)⁺.

Example 16D 7-(Trifluoromethyl)-2,3-dihydroquinolin-4(1H)-one O-methyloxime

Methoxylamine hydrochloride (4.14 g, 49.5 mmol) was added to a solutionof Example 16C (9.69 g, 45.0 mmol) in pyridine (40 mL), and mixture wasstirred overnight at ambient temperature. Only one regioisomer,7-(trifluoromethyl)-2,3-dihydroquinolin-4(1H)-one was converted to theoxime. The mixture was concentrated under reduced pressure and ethylacetate (300 mL) was added. The organic layer was washed twice withwater (300 mL) and brine, dried over sodium sulfate, and concentrateunder reduced pressure. The residue was chromatographed on silica geleluting with 20-70% ethyl acetate in hexane to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.70 (t, J=6.61 Hz, 2H), 3.19(td, J=6.53, 1.86 Hz, 2H), 3.90 (s, 3H), 6.57 (s, 1H), 6.82 (dd, J=8.14,1.70 Hz, 1H), 6.97 (s, 1H), 7.79 (d, J=8.14 Hz, 1H). MS (DCI) m/z 245.05(M+H)⁺.

Example 16E 1-Benzyl-7-(trifluoromethyl)-2,3-dihydroquinolin-4(1H)-oneO-methyl oxime

A mixture of Example 16D (1.71 g, 7.0 mmol), benzyl bromide (0.88 mL,7.35 mmol), diisopropylethylamine (2.44 mL, 14.0 mmol) in acetonitrile(12 mL) were heated in a microwave Personal Chemistry at 150° C. for 40minutes. Ethyl acetate (200 mL) was added and the organic layer waswashed twice with water (200 mL) and brine, dried over sodium sulfate,filtered, concentrate under reduced pressure, and chromatographed onsilica gel eluting with 0-10% ethyl acetate in hexane to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.84 (t, J=6.61 Hz, 2H),3.39 (t, J=6.61 Hz, 2H), 3.93 (s, 3H), 4.60 (s, 2H), 6.90 (m, 2H), 7.31(m, 5H), 7.90 (d, J=8.81 Hz, 1H). MS (DCI) m/z 335.10 (M+H)⁺.

Example 16F1-Benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-amine

Example 16E (2.10 g, 6.28 mmol) was added to a mixture of 20% ammonia inmethanol (100 mL) and Raney nickel (21 g) in a Parr shaker. The glassreactor was sealed and flushed with nitrogen, and pressurized withhydrogen (60 psi). The mixture was shaken at ambient temperature for 4hours. The solids were filtered off, washed with methanol, and thefiltrate was concentrated under reduced pressure to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.48 (br s, 2H), 1.88 (m, 1H),2.07 (m, 1H), 3.37 (m, 1H), 3.53 (m, 1H), 4.06 (br s, 1H), 4.54 (s, 2H),6.75 (s, 1H), 6.86 (d, J=7.80 Hz, 1H), 7.31 (m, 6H). MS (DCI) m/z 307.1(M+H)⁺.

Example 16GN-[1-Benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

Di(N-succinimidyl)carbonate (538 mg, 2.1 mmol) was suspended inacetonitrile (5 mL) followed by the addition of Example 1G (555 mg, 2.0mmol) dissolved in acetonitrile (5 mL) and pyridine (0.17 mL, 2.1 mmol).The mixture stirred for 15 minutes at ambient temperature after whichExample 16F (613 mg, 2.0 mmol) dissolved in acetonitrile (10 mL) anddiisopropylethylamine (1.05 mL, 6.0 mmol) was added and the mixturestirred for 30 minutes. The mixture was concentrated under reducedpressure and chromatographed on silica gel eluting with 0-to-30% ethylacetate in hexane, to afford1-(1-benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl)-3-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL), andtetrabutylammonium fluoride (1.0M in THF, 4.0 mL, 4.0 mmol) was addedand the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and chromatographed on silicagel eluting with 0-to-10% methanol in ethyl acetate. The residue wassuspended in methanol (30 mL), sonicated, and water was added (300 mL).The sonication was repeated and the solids were collected by filtration,rinsed with water, and freeze-dried to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.59 (m, 1H), 1.87 (m, 1H), 2.04 (m, 2H), 2.31(m, 1H), 2.76 (m, 3H), 3.50 (m, 2H), 3.92 (m, 1H), 4.63 (d, J=3.05 Hz,2H), 4.86 (d, J=4.07 Hz, 1H), 4.89 (m, 1H), 6.72 (m, 2H), 6.84 (d,J=7.46 Hz, 1H), 7.00 (t, J=7.80 Hz, 1H), 7.04 (d, J=7.46 Hz, 1H), 7.27(m, 3H), 7.35 (m, 3H), 7.51 (s, 1H), 7.75 (d, J=9.15 Hz, 1H). MS (ESI)m/z 496.2 (M+H)⁺. Calcd for C₂₈H₂₈F₃N₃O₂.0.04 H₂O: C, 67.77; H, 5.70; N,8.47. Found: C, 67.79; H, 5.85; N, 8.41.

Example 17N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)ureaExample 17A 1-Methyl-2,3-dihydroquinolin-4(1H)-one

Example 15B (1.62 g, 11.0 mmol), iodomethane (0.72 mL, 11.55 mmol),potassium carbonate (1.52 g, 11.0 mmol) in dimethylformamide (12 mL)were heated in a microwave at 120° C. for 1 hour. Ethyl acetate (200 mL)was added and the mixture was washed twice with water (200 mL) andbrine, dried over sodium sulfate, filtered, and concentrate underreduced pressure. The residue was chromatographed on silica gel elutingwith 10-60% ethyl acetate in hexane to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 2.63 (t, J=6.95 Hz, 2H), 2.94 (s, 3H), 3.45 (t,J=6.95 Hz, 2H), 6.71 (t, J=6.95 Hz, 1H), 6.84 (d, J=8.48 Hz, 1H), 7.42(ddd, J=8.56, 7.04, 1.70 Hz, 1H), 7.68 (dd, J=7.80, 2.03 Hz, 1H). MS(DCI) m/z 162.05 (M+H)⁺.

Example 17B 1-Methyl-2,3-dihydroquinolin-4(1H)-one O-methyl oxime

Methoxylamine hydrochloride (0.88 g, 10.6 mmol) was added to a solutionof Example 17A (1.55 g, 9.6 mmol) in pyridine (20 mL) and the mixturestirred overnight at ambient temperature. The mixture was concentratedunder reduced pressure and ethyl acetate (200 mL) was added. The organiclayer was washed twice with water (200 mL) and brine, dried over sodiumsulfate, filtered, and concentrate under reduced pressure. The residuewas chromatographed on silica gel eluting with 0-20% ethyl acetate inhexane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.76 (t, J=6.61 Hz, 2H), 2.83 (s, 3H), 3.11 (t, J=6.61 Hz, 2H), 3.87 (s,3H), 6.69 (t, J=7.46 Hz, 1H), 6.75 (d, J=8.48 Hz, 1H), 7.22 (td, J=7.80,1.70 Hz, 1H), 7.73 (dd, J=7.80, 1.70 Hz, 1H). MS (DCI) m/z 191.07(M+H)⁺.

Example 17C 1-Methyl-1,2,3,4-tetrahydroquinolin-4-amine

Example 17B (1.72 g, 9.06 mmol) was added to a mixture of 20% ammonia inmethanol (100 mL) and Raney nickel (18 g) in a Parr shaker. The glassreactor was sealed and flushed with nitrogen and pressurized withhydrogen (60 psi). The mixture was shaken at ambient temperature for 4hours. The solids were filtered off, washed with methanol and thefiltrate was concentrated under reduced pressure to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.46 (br s, 2H), 1.83 (m, 1H),2.07 (m, 1H), 2.91 (s, 3H), 3.20 (m, 1H), 3.33 (ddd, J=11.53, 10.00,3.56 Hz, 1H), 3.98 (m, 1H), 6.62 (d, J=8.48 Hz, 1H), 6.66 (t, J=7.46 Hz,1H), 7.13 (m, 1H), 7.19 (d, J=7.46 Hz, 1H). MS (DCI) m/z 163.1 (M+H)⁺.

Example 17DN-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)urea

To a mixture of Di(N-succinimidyl)carbonate (538 mg, 2.1 mmol) suspendedin acctonitrile (5 mL) was added Example 1G (555 mg, 2.0 mmol) dissolvedin acctonitrile (5 mL) and pyridine (0.17 mL, 2.1 mmol). The mixturestirred for 15 minutes at ambient temperature after which Example 17C(326 mg, 2.0 mmol) dissolved in acetonitrile (10 mL) anddiisopropylethylamine (1.05 mL, 6.0 mmol) were added and the mixturestirred for 30 minutes. The mixture was concentrated under reducedpressure and chromatographed on silica gel eluting with 10-40% ethylacetate in hexane, affording1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL), andtetrabutylammonium fluoride (1.0M in THF, 4.0 mL, 4.0 mmol) was added,and the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and chromatographed on silicagel eluting with 0-10% methanol in ethyl acetate. The residue wasdissolved in methanol (30 mL), sonicated, and water was added (300 mL).The sonication was repeated and the solids were collected by filtration,rinsed with water, and freeze-dried overnight to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.57 (m, 1H), 1.85 (m, 1H),1.94 (m, 2H), 2.29 (dd, J=16.45, 7.63 Hz, 1H), 2.73 (m, 3H), 2.87 (s,3H), 3.22 (m, 2H), 3.91 (m, 1H), 4.75 (m, 1H), 4.84 (d, J=4.07 Hz, 1H),6.63 (m, 3H), 6.94 (d, J=7.46 Hz, 1H), 6.99 (t, J=7.97 Hz, 1H), 7.10 (m,2H), 7.45 (s, 1H), 7.76 (d, J=8.14 Hz, 1H). MS (ESI) m/z 352.1 (M+H)⁺.Calcd for C₂₁H₂₅N₃O₂.0.24 H₂O: C, 70.90; H, 7.22; N, 11.81. Found: C,70.91; H, 7.21; N, 11.63.

Example 18N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]ureaExample 18A 1-Methyl-7-(trifluoromethyl)-2,3-dihydroquinolin-4(1H)-oneO-methyl oxime

Example 16D (2.20 g, 9.0 mmol), iodomethane (0.60 mL, 9.45 mmol) andpotassium carbonate (1.25 g, 9.0 mmol) in dimethylformamide (12 mL) wereheated in a microwave Personal Chemistry at 120° C. for 30 minutes.Ethyl acetate (200 mL) was added and the organic layer was washed twicewith water (200 mL), brine, dried over sodium sulfate, filtered, andconcentrate under reduced pressure. The residue was chromatographed onsilica gel eluting with 0-10% ethyl acetate in hexane to afford thetitle compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 2.88 (t, J=6.61 Hz, 2H),2.93 (s, 3H), 3.20 (t, J=6.61 Hz, 2H), 3.99 (s, 3H), 6.86 (s, 1H), 6.94(d, J=7.80 Hz, 1H), 7.99 (d, J=8.14 Hz, 1H). MS (DCI) m/z 259.05 (M+H)⁺.

Example 18B1-Methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-amine

Example 18A (1.95 g, 7.55 mmol) was added to a mixture of 20% ammonia inmethanol (100 mL) and Raney nickel (20 g) in a Parr shaker. The glassreactor was sealed and flushed with nitrogen and pressurized withhydrogen (60 psi). The mixture was shaken at ambient temperature for 4hours. The solids were filtered off, washed with methanol, and thefiltrate was concentrated under reduced pressure to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.84 (m, 1H), 2.05 (m, 1H), 2.95(s, 3H), 3.26 (m, 1H), 3.40 (ddd, J=11.70, 9.66, 4.07 Hz, 1H), 4.00 (t,J=4.75 Hz, 1H), 6.76 (s, 1H), 6.87 (d, J=7.80 Hz, 1H), 7.28 (d, J=7.80Hz, 1H). MS (DCI) m/z 231.0 (M+H)⁺.

Example 18CN-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]urea

To a mixture of Di(N-succinimidyl)carbonate (538 mg, 2.1 mmol) suspendedin acetonitrile (5 mL) was added Example 1G (555 mg, 2.0 mmol) dissolvedin acetonitrile (5 mL) and pyridine (0.17 mL, 2.1 mmol) and the mixturestirred for 15 minutes at ambient temperature. Example 18B (460 mg, 2.0mmol) dissolved in acetonitrile (10 mL) and diisopropylethylamine (1.05mL, 6.0 mmol) were added and the mixture stirred for 30 minutes. Themixture was concentrated under reduced pressure and the residue waschromatographed on silica gel eluting with 10-40% ethyl acetate inhexane, to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL),tetrabutylammonium fluoride (1.0M in THF, 4.0 mL, 4.0 mmol) was addedand the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and the residue waschromatographed on silica gel eluting with 0-10% methanol in ethylacetate. The residue was suspended in methanol (30 mL), sonicated, andwater (300 mL) was added. The sonication was repeated and the solidswere collected by filtration, rinsed with water, and freeze-dried toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.57 (m, 1H),1.86 (m, 1H), 1.96 (m, 2H), 2.30 (dd, J=16.78, 7.97 Hz, 1H), 2.76 (m,3H), 2.94 (s, 3H), 3.91 (m, 1H), 4.83 (m, 2H), 6.70 (d, J=6.78 Hz, 1H),6.81 (s, 1H), 6.88 (d, J=7.80 Hz, 1H), 6.99 (m, 2H), 7.30 (d, J=7.80 Hz,1H), 7.47 (s, 1H), 7.74 (d, J=7.80 Hz, 1H). MS (ESI) m/z 420.2 (M+H)⁺.Calcd for C₂₂H₂₄F₃N₃O₂.0.06 H₂O: C, 62.84; H, 5.78; N, 9.99. Found: C,62.86; H, 5.78; N, 9.92.

Example 19N-(1-Benzyl-1,2,3,4-tetrahydroquinolin-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 19A Ethyl 1,2,3,4-tetrahydroquinoline-3-carboxylate

Ethyl quinoline-3-carboxylate (Aldrich, 15.44 g, 76.7 mmol) was added toa mixture of ethanol (150 mL) and 10% palladium on carbon (3.0 g) in aParr shaker. The glass reactor was sealed and flushed with nitrogen, andpressurized with hydrogen (60 psi). The mixture was shaken at 50° C. for52 hours. The solids were filtered, rinsed with methanol, concentrateunder reduced pressure, and chromatographed on silica gel eluting with5-40% ethyl acetate in hexane to afford the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.19 (t, J=7.12 Hz, 3H), 2.83 (m, 3H), 3.17 (m, 1H),3.39 (m, 1H), 4.09 (q, J=7.12 Hz, 2H), 5.74 (s, 1H), 6.44 (m, 2H), 6.86(m, 2H). MS (DCI) m/z 206.10 (M+H)⁺.

Example 19B Ethyl 1-benzyl-1,2,3,4-tetrahydroquinoline-3-carboxylate

Example 19A (6.16 g, 30.0 mmol), benzyl bromide (3.57 mL, 30.0 mmol) anddiisopropylethylamine (10.5 mL, 60.0 mmol) in acetonitrile (40 mL) wereheated in a microwave at 150° C. for 30 minutes. Ethyl acetate (400 mL)was added and the separated organic layer was washed twice with water(400 mL), brine, dried over sodium sulfate, filtered, and concentrateunder reduced pressure. The residue was chromatographed on silica geleluting with 0-20% ethyl acetate in hexane to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.17 (t, J=7.12 Hz, 3H), 2.96 (m, 3H),3.48 (m, 2H), 4.09 (q, J=7.12 Hz, 2H), 4.49 (d, J=7.45 Hz, 2H), 6.49 (m,2H), 6.89 (m, 1H), 6.97 (d, J=7.12 Hz, 1H), 7.26 (m, 5H). MS (DCI) m/z296.12 (M+H)⁺.

Example 19C 1-Benzyl-1,2,3,4-tetrahydroquinoline-3-carboxylic acid

Example 19B (8.84 g, 29.9 mmol) was dissolved in tetrahydrofuran (300mL), 1.0N lithium hydroxide (300 mL) was added and the mixture stirredovernight at ambient temperature. The organic layer was concentratedunder reduced pressure and the aqueous layer was neutralized with citricacid (18.12 g, 94.3 mmol) and they were recombined. Water (100 mL) wasadded and the mixture was extracted twice with ethyl acetate (300 mL),and brine, filtered, and dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 2.88 (m, 3H), 3.49 (m, 2H), 4.49 (s, 2H), 6.48(m, 2H), 6.88 (t, J=8.14 Hz, 1H), 6.95 (d, J=7.29 Hz, 1H), 7.27 (m, 5H).MS (DCI) m/z 268.10 (M+H)⁺.

Example 19D tert-Butyl 1-benzyl-1,2,3,4-tetrahydroquinolin-3-ylcarbamate

Example 19C (7.75 g, 29.0 mmol), diphenylphosphoryl azide (6.89 mL, 31.9mmol), triethylamine (4.85 mL, 34.8 mmol) in tert-butanol (200 mL) wereheated at 110° C. for 9 hours. After cooling, the mixture wasconcentrated under reduced pressure and diluted with 1:1 ethylacetate:hexane (200 mL). The crystals were filtered off, the filtratewas concentrate under reduced pressure, and the residue waschromatographed on silica gel eluting with 0-30% ethyl acetate in hexaneto afford the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.42 (s,9H), 2.74 (d, J=16.61 Hz, 1H), 3.13 (d, J=16.11 Hz, 1H), 3.30 (d, J=9.16Hz, 1H), 3.52 (d, J=12.04 Hz, 1H), 4.21 (br s, 1H), 4.49 (s, 2H), 4.82(br s, 1H), 6.58 (d, J=8.14 Hz, 1H), 6.63 (t, J=7.46 Hz, 1H), 7.01 (m,2H), 7.29 (m, 5H). MS (ESI) m/z 339.1 (M+H)⁺.

Example 19E 1-Benzyl-1,2,3,4-tetrahydroquinolin-3-amine

Example 19D (1.36 g, 4.0 mmol) was dissolved in dichloromethane (10 mL),and trifluoroacetic acid (2 mL) was added and the mixture stirredovernight at ambient temperature. The mixture was concentrated underreduced pressure and 1.0N sodium hydroxide (100 mL) was added. Themixture was extracted twice with ethyl acetate (100 mL). The combindedorganic layers were washed with brine, dried over sodium sulfate andfiltered. The solvent was evaporated to afford the title compound. ¹HNMR (300 MHz, CDCl₃) δ ppm 2.65 (dd, J=15.60, 7.46 Hz, 1H), 3.09 (m,2H), 3.41 (m, 2H), 4.48 (d, J=6.45 Hz, 2H), 6.56 (d, J=8.81 Hz, 1H),6.61 (t, J=7.29 Hz, 1H), 7.00 (m, 2H), 7.27 (m, 5H). MS (DCI) m/z 239.08(M+H)⁺.

Example 19FN-(1-Benzyl-1,2,3,4-tetrahydroquinolin-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

Di(N-succinimidyl)carbonate (578 mg, 2.26 mmol) was dissolved inacetonitrile (5 mL) followed by the addition of Example 1G (596 mg, 2.15mmol) dissolved in acctonitrile (5 mL) and pyridine (0.18 mL, 2.26mmol). The mixture was stirred for 15 minutes at ambient temperatureafter which Example 19E (512 mg, 2.15 mmol) dissolved in acetonitrile(10 mL) and diisopropylethylamine (1.12 mL, 6.44 mmol) were added andthe mixture was stirred for 30 minutes. The mixture was concentratedunder reduced pressure and the residue was chromatographed on silica geleluting with 0-30% ethyl acetate in hexane to afford1-(1-benzyl-1,2,3,4-tetrahydroquinolin-3-yl)-3-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL) andtetrabutylammonium fluoride (1.0M in THF, 4.3 mL, 4.3 mmol) was added,and the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and chromatographed on silicagel eluting with 0-10% methanol in ethyl acetate. The residue wassuspended in methanol (20 mL), sonicated, and additional water (200 mL)was added. The sonication was repeated and the solids were collected byfiltration, rinsed with water, and freeze-dried to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.57 (m, 1H), 1.86 (m, 1H),2.31 (m, 1H), 2.74 (m, 4H), 3.08 (m, 1H), 3.52 (d, J=10.85 Hz, 1H), 3.91(m, 1H), 4.17 (m, 1H), 4.51 (s, 2H), 4.85 (m, 1H), 6.51 (d, J=8.14 Hz,1H), 6.54 (t, J=7.29 Hz, 1H), 6.69 (d, J=7.46 Hz, 1H), 6.75 (d, J=7.46Hz, 1H), 6.95 (m, 3H), 7.21 (m, 1H), 7.30 (d, J=4.41 Hz, 4H), 7.65 (d,J=8.13 Hz, 1H), 7.67 (d, J=2.71 Hz, 1H). MS (ESI) m/z 428.29 (M+H)⁺.Calcd for C₂₇H₂₉N₃O₂.0.24 H₂O: C, 75.09; H, 6.88; N, 9.73. Found: C,75.12; H, 6.90; N, 9.64.

Example 20N-[1-Benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 20A Ethyl 4-chloro-7-(trifluoromethyl)quinoline-3-carboxylate

Ethyl 4-hydroxy-7-(trifluoromethyl)quinoline-3-carboxylate (Aldrich,10.0 g, 35.1 mmol) and phosphorus oxychloride (100 mL, 1.07 mol) wererefluxed for 2 hours. After cooling the mixture was poured onto ice (1.0L) and stirred for 1 hour. The mixture was extracted twice withdichloromethane (500 mL), dried over sodium sulfate, and concentratedunder reduced pressure. The residue was chromatographed on silica geleluting with 0-40% ethyl acetate in hexane to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.40 (t, J=7.12 Hz, 3H), 4.46 (q, J=7.12Hz, 2H), 8.14 (d, J=8.82 Hz, 1H), 8.54 (s, 1H), 8.62 (d, J=8.82 Hz, 1H),9.30 (s, 1H). MS (ESI) m/z 303.95 (M+H)⁺.

Example 20B Ethyl7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-3-carboxylate

Example 20A (8.55 g, 28.0 mmol) was added to a mixture oftetrahydrofuran (100 mL), ethanol (200 mL), and 5% palladium on carbon(1.7 g) in a Parr shaker. The glass reactor was sealed and flushed withnitrogen and pressurized with hydrogen (60 psi). The mixture was shakenat 50° C. for 16 hours after which the solids were filtered, rinsed withmethanol, and the filtrated concentrated under reduced pressure. Ethylacetate (200 mL) was added and the organic layer was washed withsaturated sodium bicarbonate (200 mL), brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waschromatographed on silica gel eluting with 0-40% ethyl acetate in hexaneto afford the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.27 (t,J=7.12 Hz, 3H), 2.90 (m, 1H), 3.03 (d, J=7.46 Hz, 2H), 3.41 (dd,J=11.52, 8.81 Hz, 1H), 3.58 (dd, J=11.53, 3.73 Hz, 1H), 4.06 (br s, 1H),4.19 (q, J=7.23 Hz, 2H), 6.71 (s, 1H), 6.85 (d, J=8.14 Hz, 1H), 7.07 (d,J=7.80 Hz, 1H). MS (DCI) m/z 274.05 (M+H)⁺.

Example 20C Ethyl1-benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-3-carboxylate

Example 20B (4.10 g, 15.0 mmol), benzyl bromide (1.78 mL, 15.0 mmol) anddiisopropylethylamine (5.22 mL, 30.0 mmol) in acetonitrile (20 mL) wereheated in a microwave at 150° C. for 30 minutes. Ethyl acetate (200 mL)was added, and the organic layer was washed twice with water (200 mL),brine, dried over sodium sulfate, filtered, and concentrate underreduced pressure. The residue was chromatographed on silica gel elutingwith 0-20% ethyl acetate in hexane to afford the title compound. ¹H NMR(300 MHz, CDCl₃) δ ppm 1.25 (t, J=7.12 Hz, 3H), 2.98 (m, 1H), 3.08 (d,J=7.12 Hz, 2H), 3.54 (m, 2H), 4.16 (qd, J=7.12, 2.03 Hz, 2H), 4.53 (s,2H), 6.77 (s, 1H), 6.85 (d, J=7.46 Hz, 1H), 7.10 (d, J=7.46 Hz, 1H),7.25 (m, 2H), 7.31 (m, 3H). MS (DCI) m/z 364.14 (M+H)⁺.

Example 20D1-Benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-3-carboxylicacid

Example 20C (5.15 g, 14.2 mmol) was dissolved in tetrahydrofuran (150mL), and 1.0N lithium hydroxide (150 mL) was added. The mixture wasstirred overnight at ambient temperature. The organic layer wasseparated, the aqueous layer was neutralized with citric acid (6.68 g,34.8 mmol) and they were recombined. Water (100 mL) was added and themixture was extracted twice with ethyl acetate (300 mL). The combinedorganic layers were washed with brine and dried over sodium sulfate, andconcentrated under reduced pressure to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 2.99 (m, 3H), 3.58 (m, 2H), 4.57 (s, 2H), 6.66(s, 1H), 6.79 (d, J=7.80 Hz, 1H), 7.17 (d, J=7.80 Hz, 1H), 7.28 (m, 5H),12.58 (br s, 1H). MS (DCI) m/z 336.08 (M+H)⁺.

Example 20E tert-Butyl1-benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate

Example 20D (4.63 g, 13.8 mmol), diphenylphosphoryl azide (3.3 mL, 15.2mmol) and triethylamine (2.31 mL, 16.6 mmol) in tert-butanol (100 mL)were heated at 100° C. for 4.5 hours. After cooling, the mixture wasconcentrated under reduced pressure and chromatographed on silica geleluting with 0-30% ethyl acetate in hexane to afford the title compound.¹H NMR (300 MHz, CDCl₃) δ ppm 1.43 (s, 9H), 2.78 (dd, J=16.11, 4.24 Hz,1H), 3.12 (d, J=16.61 Hz, 1H), 3.32 (d, J=10.85 Hz, 1H), 3.54 (d,J=12.21 Hz, 1H), 4.21 (br s, 1H), 4.51 (s, 2H), 4.71 (br s, 1H), 6.80(s, 1H), 6.86 (d, J=7.80 Hz, 1H), 7.06 (d, J=7.46 Hz, 1H), 7.25 (m, 2H),7.30 (m, 3H). MS (ESI) m/z 407.1 (M+H)⁺.

Example 20F1-Benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-amine

To Example 20E (1.22 g, 3.0 mmol) dissolved in dichloromethane (10 mL)was added trifluoroacetic acid (2 mL) and the mixture stirred overnightat ambient temperature. The mixture was concentrated under reducedpressure and 1.0M potassium carbonate (100 mL), was added and themixture was extracted twice with ethyl acetate (100 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrate under reduced pressure. The residue waschromatographed on silica gel eluting with 0-10% methanol indichloromethane to afford the title compound. ¹H NMR (300 MHz, CDCl₃) δppm 2.66 (dd, J=16.28, 7.46 Hz, 1H), 3.06 (d, J=15.26 Hz, 1H), 3.14 (m,1H), 3.43 (m, 2H), 4.51 (d, J=4.07 Hz, 2H), 6.78 (s, 1H), 6.84 (m, 1H),7.06 (d, J=7.46 Hz, 1H), 7.24 (m, 2H), 7.31 (m, 3H). MS (DCI) m/z 307.08(M+H)⁺.

Example 20GN-[1-Benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

To Di(N-succinimidyl)carbonate (517 mg, 2.02 mmol) dissolved inacetonitrile (5 mL) was added Example 1G (534 mg, 1.92 mmol) dissolvedin acetonitrile (5 mL) and pyridine (0.16 mL, 2.02 mmol) and the mixturestirred for 15 minutes at ambient temperature. Example 20F (589 mg, 1.92mmol) dissolved in acctonitrile (10 mL) and diisopropylethylamine (1.0mL, 5.77 mmol) were added and the mixture stirred for 30 minutes. Themixture was concentrated under reduced pressure and the residue waschromatographed on silica gel eluting with 0-30% ethyl acetate in hexaneto afford1-(1-benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)-3-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL) andtetrabutylammonium fluoride (1.0M in THF, 3.85 mL, 3.85 mmol) was added,and the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and the residue waschromatographed on silica gel eluting with 0-10% methanol in ethylacetate. The solid was suspended in methanol (20 mL), sonicated, andwater (200 mL) was added. The sonication was repeated, and the solidswere collected by filtration, rinsed with water, and freeze-dried toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.57 (m, 1H),1.86 (m, 1H), 2.30 (dd, J=16.45, 7.63 Hz, 1H), 2.73 (m, 4H), 3.15 (d,J=16.96 Hz, 1H), 3.61 (d, J=11.53 Hz, 1H), 3.91 (m, 1H), 4.22 (m, 1H),4.58 (s, 2H), 4.86 (t, J=3.73 Hz, 1H), 6.71 (m, 2H), 6.75 (d, J=7.80 Hz,1H), 6.83 (d, J=7.80 Hz, 1H), 6.97 (t, J=7.80 Hz, 1H), 7.19 (d, J=7.80Hz, 1H), 7.23 (m, 1H), 7.31 (m, 4H), 7.66 (m, 2H). MS (DCI) m/z 496.20(M+H)⁺. Calcd for C₂₈H₂₈F₃N₃O₂.0.17 H₂O: C, 67.45; H, 5.73; N, 8.43.Found: C, 67.44; H, 5.69; N, 8.42, 6.88; N, 9.73. Found: C, 75.12; H,6.90; N, 9.64.

Example 21N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)ureaExample 21A tert-Butyl 1,2,3,4-tetrahydroquinolin-3-ylcarbamate

Example 19D (4.05 g, 12.0 mmol) was added to a mixture of methanol (100mL) and 20% palladium hydroxide on carbon (0.8 g) in a Parr shaker. Theglass reactor was sealed and flushed with nitrogen, and pressurized withhydrogen (60 psi). The mixture was shaken at ambient temperature for 16hours. The solids were filtered, rinsed with methanol, and the filtratewas concentrate under reduced pressure. The residue was chromatographedon silica gel eluting with 0-35% ethyl acetate in hexane to afford thetitle compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.43 (s, 9H), 2.71 (d,J=16.27 Hz, 1H), 3.05 (dd, J=16.45, 4.58 Hz, 1H), 3.21 (d, J=9.84 Hz,1H), 3.38 (dd, J=11.36, 2.20 Hz, 1H), 3.82 (br s, 1H), 4.17 (br s, 1H),4.98 (br s, 1H), 6.52 (d, J=7.80 Hz, 1H), 6.66 (t, J=7.29 Hz, 1H), 6.98(m, 2H). MS (DCI) m/z 249.11 (M+H)⁺.

Example 21B tert-Butyl 1-methyl-1,2,3,4-tetrahydroquinolin-3-ylcarbamate

Example 21A (880 mg, 3.54 mmol), sodium bicarbonate (536 mg, 6.38 mmol),dimethoxyethane (7 mL) and water (7 mL) were combined and dimethylsulfate (0.44 mL, 4.61 mmol) was added and the mixture stirred overnightat ambient temperature. Ethyl acetate (200 mL) was added and theseparated organic layer was washed with saturated sodium bicarbonate(200 mL), brine, dried over sodium sulfate, filtered and concentrateunder reduced pressure. The residue was chromatographed on silica geleluting with 5-35% ethyl acetate in hexane to afford the title compound.¹H NMR (300 MHz, CDCl₃) δ ppm 1.43 (s, 9H), 2.73 (d, J=16.27 Hz, 1H),2.90 (s, 3H), 3.08 (m, 2H), 3.37 (d, J=13.56 Hz, 1H), 4.19 (br s, 1H),4.94 (br s, 1H), 6.65 (m, 2H), 6.98 (d, J=7.12 Hz, 1H), 7.12 (t, J=7.80Hz, 1H). MS (DCI) m/z 263.13 (M+H)⁺.

Example 21C 1-Methyl-1,2,3,4-tetrahydroquinolin-3-amine

Example 21B (980 mg, 3.74 mmol) was dissolved in dichloromethane (15mL), and trifluoroacetic acid (3 mL) was added and the mixture stirredfor 3 hours at ambient temperature. The mixture was concentrated underreduced pressure to afford the title compound. MS (DCI) m/z 163.08(M+H)⁺.

Example 21DN-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)urea

To Di(N-succinimidyl)carbonate (1.01 g, 3.92 mmol) dissolved inacetonitrile (5 mL) was added Example 1G (1.04 g, 3.74 mmol) inacetonitrile (10 mL) and pyridine (0.32 mL, 3.92 mmol) and the mixturestirred for 15 minutes at ambient temperature. Example 21C (2.75 g)dissolved in acetonitrile (15 mL) and diisopropylethylamine (5.2 mL,29.9 mmol) were added and the mixture stirred for 2 hours. Ethyl acetate(200 mL) and saturated sodium bicarbonate (200 mL) were added and theorganic layer was washed with brine, dried over sodium sulfate,filtered, and concentrate under reduced pressure. The residue waschromatographed on silica gel eluting with 10-40% ethyl acetate inhexane, to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL),tetrabutylammonium fluoride (1.0M in THF, 6.5 mL, 6.5 mmol) was addedand the mixture was stirred overnight at ambient temperature. Themixture was concentrated under reduced pressure and the residue waschromatographed on silica gel eluting with 0-10% methanol in ethylacetate. The residue was suspended in methanol (20 mL), sonicated, andwater (200 mL) was added. The sonication was repeated, and the solidswere collected by filtration, rinsed with water, and freeze-driedovernight to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.56 (m, 1H), 1.84 (m, 1H), 2.28 (dd, J=16.62, 7.80 Hz, 1H), 2.71 (m,4H), 2.87 (s, 3H), 3.03 (m, 2H), 3.36 (m, 1H), 3.89 (m, 1H), 4.12 (m,1H), 4.81 (d, J=3.05 Hz, 1H), 6.59 (t, J=7.29 Hz, 1H), 6.64 (d, J=8.13Hz, 1H), 6.68 (d, J=7.46 Hz, 1H), 6.74 (d, J=7.80 Hz, 1H), 6.94 (d,J=7.12 Hz, 1H), 6.97 (t, J=7.80 Hz, 1H), 7.04 (m, 1H), 7.61 (s, 1H),7.68 (d, J=8.14 Hz, 1H). MS (ESI) m/z 352.17 (M+H)⁺. Calcd forC₂₁H₂₅N₃O₂: C, 71.77; H, 7.17; N, 11.96. Found: C, 71.77; H, 7.16; N,11.77.

Example 22N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-1)-N′-[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]ureaExample 22A tert-Butyl7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate

Example 20E (2.73 g, 6.71 mmol) was added to a mixture of methanol (60mL) and 20% palladium hydroxide on carbon (0.55 g) in a Parr shaker. Theglass reactor was sealed and flushed with nitrogen, and pressurized withhydrogen (60 psi). The mixture was shaken at ambient temperature for 16hours. The solids were filtered, rinsed with methanol, and the filtratewas concentrate under reduced pressure. The residue was chromatographedon silica gel eluting with 0-40% ethyl acetate in hexane to afford thetitle compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.44 (s, 9H), 2.76 (d,J=16.61 Hz, 1H), 3.05 (dd, J=16.79, 3.90 Hz, 1H), 3.25 (d, J=10.51 Hz,1H), 3.42 (d, J=11.53, 1H), 4.01 (s, 1H), 4.18 (br s, 1H), 4.86 (br s,1H), 6.73 (s, 1H), 6.87 (d, J=7.80 Hz, 1H), 7.04 (d, J=7.80 Hz, 1H). MS(DCI) m/z 317.10 (M+H)⁺.

Example 22B tert-Butyl1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate

Example 22A (1.27 g, 4.0 mmol), iodomethane (0.25 mL, 4.0 mmol) andpotassium carbonate (553 mg, 4.0 mmol) in dimethylformamide (12 mL) wereheated in a microwave Personal Chemistry at 120° C. for 15 minutes.Ethyl acetate (200 mL) was added, and the separated organic layer washedwith saturated sodium bicarbonate (200 mL), brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure to afford thetitle compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.44 (s, 9H), 2.77 (d,J=16.61 Hz, 1H), 2.94 (s, 3H), 3.06 (dd, J=16.61, 4.07 Hz, 1H), 3.15(ddd, J=11.53, 4.75, 2.03 Hz, 1H), 3.43 (dd, J=11.36, 2.54 Hz, 1H), 4.20(br s, 1H), 4.81 (br s, 1H), 6.79 (s, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.04(d, J=7.12 Hz, 1H). MS (DCI) m/z 331.10 (M+H)⁺.

Example 22C1-Methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-amine

Example 22B (1.00 g, 3.03 mmol) was dissolved in dichloromethane (15mL), and trifluoroacetic acid (3 mL) was added and the mixture stirredfor 2 hours at ambient temperature. The mixture was concentrated underreduced pressure to afford the title compound. MS (DCI) m/z 231.06(M+H)⁺.

Example 22DN-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]urea

To Di(N-succinimidyl)carbonate (816 mg, 3.18 mmol) in acetonitrile (5mL) was added Example 1G (842 mg, 3.03 mmol) in acetonitrile (10 mL) andpyridine (0.26 mL, 3.18 mmol) and the mixture stirred for 15 minutes atambient temperature. Example 22C (1.86 g) dissolved in acetonitrile (15mL) and diisopropylethylamine (4.2 mL, 24.2 mmol) were added and themixture stirred overnight. Ethyl acetate (200 mL) was added and theseparated organic layer was washed with saturated sodium bicarbonate(200 mL), brine, dried over sodium sulfate, filtered, and concentrateunder reduced pressure. The residue was chromatographed on silica gelcluting with 10-40% ethyl acetate in hexane, to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL),tetrabutylammonium fluoride (1.0M in THF, 5.4 mL, 5.4 mmol) was added,and the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and chromatographed on silicagel eluting with 0-10% methanol in ethyl acetate. The residue wassuspended methanol (20 mL), sonicated, and water (200 mL) was added. Thesonication was repeated, and the solids were collected by filtration,rinsed with water, and freeze-dried to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.56 (m, 1H), 1.84 (m, 1H), 2.27 (dd, J=116.78,7.29 Hz, 1H), 2.73 (m, 4H), 2.94 (s, 3H), 3.06 (dd, J=16.11, 4.24 Hz,1H), 3.15 (dd, J=11.36, 5.26 Hz, 1H), 3.45 (dd, J=11.19, 3.05 Hz, 1H),3.89 (m, 1H), 4.16 (m, 1H), 4.81 (d, J=3.73 Hz, 1H), 6.69 (d, J=7.46 Hz,1H), 6.74 (d, J=7.46 Hz, 1H), 6.81 (s, 1H), 6.87 (d, J=7.80 Hz, 1H),6.97 (t, J=7.80 Hz, 1H), 7.15 (d, J=7.80 Hz, 1H), 7.58 (s, 1H), 7.68 (d,J=7.80 Hz, 1H). MS (ESI) m/z 420.23 (M+H)⁺. Calcd for C₂₂H₂₄F₃N₃O₂: C,63.00; H, 5.77; N, 10.02. Found: C, 62.96; H, 5.59; N, 9.89.

Example 23N-[(1-Benzyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 23A Ethyl quinoline-2-carboxylate

Quinoline-2-carboxylic acid (Aldrich, 10.0 g, 57.7 mmol) was added toethanol (500 mL) and sulfuric acid (25 mL) and refluxed for 7 hours. Themixture was concentrated under reduced pressure and dichloromethane (400mL) was added. The organic layer was washed twice with saturated sodiumbicarbonate (400 mL), dried with sodium sulfate, filtered andconcentrated under reduced pressure to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.39 (t, J=7.12 Hz, 3H), 4.43 (q, J=7.12 Hz,2H), 7.76 (ddd, J=8.14, 6.95, 1.19 Hz, 1H), 7.88 (ddd, J=8.48, 6.95,1.53 Hz, 1H), 8.11 (m, 2H), 8.18 (d, J=8.48 Hz, 1H), 8.58 (d, J=8.48 Hz,1H). MS (DCI) m/z 202.05 (M+H)⁺.

Example 23B Ethyl 1,2,3,4-tetrahydroquinoline-2-carboxylate

Example 23A (10.77 g, 53.5 mmol) was added to a mixture of acetic acid(400 mL) and 5% platinum on carbon (2.0 g) in a Parr shaker. The glassreactor was sealed and flushed with nitrogen, and pressurized withhydrogen (60 psi). The mixture was shaken at ambient temperature for 2hours. The solids were filtered, rinsed with methanol and the filtratewas concentrate under reduced pressure. Ethyl acetate (200 mL) was addedand the organic layer was washed with saturated sodium bicarbonate (200mL) and brine, dried over sodium sulfate, filtered and concentrate underreduced pressure. The residue was chromatographed on silica gel elutingwith 0-25% ethyl acetate in hexane to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.20 (t, J=7.12 Hz, 3H), 1.98 (q, J=6.27 Hz,2H), 2.56 (t, J=7.29 Hz, 1H), 2.67 (dt, J=16.36, 5.89 Hz, 1H), 4.02 (td,J=5.17, 2.54 Hz, 1H), 4.12 (qd, J=7.12, 1.70 Hz, 2H), 5.93 (d, J=2.03Hz, 1H), 6.44 (td, J=7.46, 1.02 Hz, 1H), 6.55 (d, J=7.80 Hz, 1H), 6.84(m, 2H). MS (DCI) m/z 206.10 (M+H)⁺.

Example 23C Ethyl 1-benzyl-1,2,3,4-tetrahydroquinoline-2-carboxylate

Example 23B (2.46 g, 12.0 mmol), benzyl bromide (1.5 mL, 12. mmol) anddiisopropylethylamine (4.2 mL, 24.0 mmol) in acetonitrile (16 mL) wereheated in a microwave at 150° C. for 30 minutes. Ethyl acetate (200 mL)was added and the separated organic layer was washed twice with water(200 mL), brine, dried over sodium sulfate, filtered, and concentrateunder reduced pressure. The residue was chromatographed on silica geleluting with 0-20% ethyl acetate in hexane to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.17 (t, J=6.96 Hz, 3H), 2.11 (m, 1H),2.28 (m, 1H), 2.61 (dd, J=12.89, 5.09 Hz, 1H), 2.70 (d, J=16.28 Hz, 1H),4.10 (t, J=7.46 Hz, 2H), 4.30 (t, J=3.57 Hz, 1H), 4.36 (d, J=17.29 Hz,1H), 4.63 (d, J=16.95 Hz, 1H), 6.39 (d, J=8.14 Hz, 1H), 6.50 (t, J=7.29Hz, 1H), 6.89 (m, 2H), 7.28 (m, 5H). MS (DCI) m/z 296.12 (M+H)⁺.

Example 23D 1-Benzyl-1,2,3,4-tetrahydroquinoline-2-carboxamide

Ammonia in methanol (7N, 40 mL) was added to Example 23C (3.10 g, 10.5mmol) in a stainless steel autoclave and the mixture was chilled to −75°C. Anhydrous ammonia (20 mL) was added, the reactor was sealed, and themixture was heated to 100° C. for 40 hours. The mixture was concentratedunder reduced pressure and the residue was chromatographed on silica geleluting with 50-100% ethyl acetate in hexane to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.94 (m, 1H), 2.22 (m, 1H),2.63 (m, 2H), 3.97 (dd, J=5.09, 3.05 Hz, 1H), 4.22 (d, J=17.63 Hz, 1H),4.75 (d, J=17.29 Hz, 1H), 6.41 (d, J=8.14 Hz, 1H), 6.48 (t, J=7.29 Hz,1H), 6.88 (m, 2H), 7.13 (s, 1H), 7.22 (m, 3H), 7.31 (m, 3H). MS (DCI)m/z 267.10 (M+H)⁺.

Example 23E (1-Benzyl-1,2,3,4-tetrahydroquinolin-2-yl)methanamine

Lithium aluminum hydride (1.0M in THF, 18.8 mL, 18.8 mmol) was added toExample 23D (1.67 g, 6.26 mmol) suspended in tetrahydrofuran (50 mL).The mixture stirred for 2 hours at ambient temperature and was refluxedfor 1 hour. The mixture was chilled to 0° C. followed by the sequentialaddition of water (1.6 mL), tetrahydrofuran (50 mL), 15% sodiumhydroxide (1.6 mL) and water (3.2 mL). The mixture was filtered, thesolids were rinsed with ethyl acetate (200 mL), and the combinedfiltrate was dried over sodium sulfate, filtered, and concentrated underreduced pressure to afford the title compound. ¹H NMR (300 MHz, CDCl₃) δppm 1.95 (m, 1H), 2.11 (m, 1H), 2.82 (m, 4H), 3.36 (td, J=8.39, 4.58 Hz,1H), 4.59 (d, J=6.44 Hz, 2H), 6.48 (d, J=7.46 Hz, 1H), 6.59 (t, J=7.46Hz, 1H), 6.99 (m, 2H), 7.23 (m, 2H), 7.30 (m, 2H). MS (DCI) m/z 253.12(M+H)⁺.

Example 23FN-[(1-Benzyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

To di(N-succinimidyl)carbonate (539 mg, 2.1 mmol) in acetonitrile (5 mL)was added Example 1G (556 mg, 2.0 mmol) in acetonitrile (5 mL) andpyridine (0.17 mL, 2.1 mmol) and the mixture stirred for 15 minutes atambient temperature. Example 23E (505 mg, 2.0 mmol) in acetonitrile (10mL) and diisopropylethylamine (1.05 mL, 6.0 mmol) were added and themixture stirred for 30 minutes. The mixture was concentrated underreduced pressure and the residue was chromatographed on silica geleluting with 0-30% ethyl acetate in hexane to afford1-((1-benzyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl)-3-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL), andtetrabutylammonium fluoride (1.0M in THF, 3.2 mL, 3.2 mmol) was addedand the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and the residue waschromatographed on silica gel eluting with 0-10% methanol in ethylacetate. The residue was dissolved in ethyl acetate (300 mL), washedwith water (300 mL), brine, dried over sodium sulfate, filtered,concentrate under reduced pressure, and vacuum dried overnight to affordthe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.58 (m, 1H), 1.84(m, 2H), 2.03 (m, 1H), 2.33 (dd, J=16.78, 7.63 Hz, 1H), 2.78 (m, 5H),3.12 (m, 1H), 3.49 (m, 1H), 3.91 (m, 1H), 4.62 (q, J=15.85 Hz, 2H), 4.85(d, J=4.41 Hz, 1H), 6.33 (d, J=8.13 Hz, 1H), 6.46 (td, J=7.29, 0.91 Hz,1H), 6.72 (m, 2H), 6.84 (t, J=7.80 Hz, 1H), 6.94 (dd, J=7.12, 1.02 Hz,1H), 6.97 (t, J=7.80 Hz, 1H), 7.22 (m, 3H), 7.31 (m, 2H), 7.56 (m, 2H).MS (ESI) m/z 442.28 (M+H)⁺. Calcd for C₂₈H₃₁N₃O₂.0.39 EtOAc: C, 74.60;H, 7.23; N, 8.83. Found: C, 74.58; H, 7.41; N, 8.94.

Example 24N-{[1-Benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl]methyl}-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 24A Dimethyl 2-(3-(trifluoromethyl)phenylamino)maleate

3-(Trifluoromethyl)aniline (10.0 g, 62.0 mmol) and dimethylacetylenedicarboxylate (8.4 mL, 68.4 mmol) were dissolved in methanol(100 mL) and the mixture was refluxed for 2 hours. After cooling, themixture was concentrated under reduced pressure and the residue waschromatographed on silica gel eluting with 0-30% ethyl acetate in hexaneto afford the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm 3.71 (s,3H), 3.73 (s, 3H), 5.49 (s, 1H), 7.16 (m, 2H), 7.36 (d, J=7.80 Hz, 1H),7.48 (t, J=7.80 Hz, 1H). MS (ESI) m/z 303.97 (M+H)⁺.

Example 24B Methyl4-oxo-7-(trifluoromethyl)-1,4-dihydroquinoline-2-carboxylate and Methyl4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-2-carboxylate

Example 24A (14.42 g, 47.6 mmol) in diphenyl ether (20 mL) was added in2 mL portions to diphenyl ether (150 mL) that was preheated to 245° C.The mixture was heated for 1 hour at 250° C. then cooled to ambienttemperature. Hexane (200 mL) was added to the mixture, the solids werecollected by filtration, rinsed with hexane (200 mL) and diethyl ether(100 mL), and air-dried to afford the title compound as a mixture ofregioisomers: ˜85% methyl4-oxo-7-(trifluoromethyl)-1,4-dihydroquinoline-2-carboxylate and ˜15%methyl 4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-2-carboxylate. ¹HNMR (300 MHz, CD₃OD) δ ppm 4.05 (s, 3H), 7.00 (s, 1H), 7.67 (dd, J=8.82,1.70 Hz, 1H), 8.21 (s, 1H), 8.41 (d, J=8.48 Hz, 1H). MS (ESI) m/z 271.91(M+H)⁺.

Example 24C Methyl 4-chloro-7-(trifluoromethyl)quinoline-2-carboxylate

Example 24B (9.53 g, 35.1 mmol) and phosphorus oxychloride (100 mL, 1.07mol) were refluxed for 2 hours. After cooling, the mixture was pouredonto ice (1.0 L) and stirred for 1 hour. The mixture was extracted twicewith ethyl acetate (400 mL), washed with brine, dried over sodiumsulfate, filtered, and concentrate under reduced pressure. The residuewas chromatographed on silica gel eluting with 0-40% ethyl acetate inhexane to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.99 (s, 3H), 8.19 (dd, J=8.65, 1.86 Hz, 1H), 8.41 (s, 1H), 8.52 (d,J=8.82 Hz, 1H), 8.66 (s, 1H). MS (ESI) m/z 289.94 (M+H)⁺.

Example 24D Methyl7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

Example 24C (8.21 g, 28.3 mmol) in tetrahydrofuran (8 5 mL) was added toa mixture of 5% palladium on carbon (1.7 g) and methanol (85 mL) in aParr shaker. The glass reactor was sealed and flushed with nitrogen andpressurized with hydrogen (60 psi). The mixture was shaken at 50° C. for16 hours. The solids were filtered, rinsed with methanol, and thefiltrate was concentrated under reduced pressure. Ethyl acetate (200 mL)was added, and the separated organic layer was washed with saturatedsodium bicarbonate (200 mL) and brine. The organic layer was dried oversodium sulfate, filtered, and concentrate under reduced pressure. Theresidue was chromatographed on silica gel eluting with 0-30% ethylacetate in hexane to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 2.01 (m, 2H), 2.61 (m, 1H), 2.73 (dt, J=16.95, 5.42 Hz,1H), 3.67 (s, 3H), 4.14 (td, J=5.08, 2.71 Hz, 1H), 6.53 (d, J=2.38 Hz,1H), 6.73 (dd, J=7.80, 1.36 Hz, 1H), 6.88 (d, J=1.69 Hz, 1H), 7.04 (d,J=7.80 Hz, 1H). MS (ESI) m/z 259.90 (M+H)⁺.

Example 24E Methyl1-benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

Example 24D (1.30 g, 5.0 mmol), benzyl bromide (0.6 mL, 5.0 mmol) anddiisopropylethylamine (1.74 mL, 10.0 mmol) in acetonitrile (8 mL) wereheated in a microwave at 150° C. for 1 hour. Ethyl acetate (200 mL) wasadded and the separated organic layer was washed twice with water (200mL) and brine. The organic layer was dried over sodium sulfate,filtered, and concentrate under reduced pressure. The residue waschromatographed on silica gel eluting with 0-20% ethyl acetate in hexaneto afford the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 2.14 (m,1H), 2.39 (dq, J=13.35, 3.69 Hz, 1H), 2.77 (dd, J=8.99, 3.56 Hz, 2H),3.72 (s, 3H), 4.18 (dd, J=5.26, 2.88 Hz, 1H), 4.32 (d, J=16.95 Hz, 1H),4.79 (d, J=16.95 Hz, 1H), 6.78 (s, 1H), 6.86 (d, J=7.80 Hz, 1H), 7.05(d, J=7.80 Hz, 1H), 7.24 (m, 2H), 7.31 (m, 3H). MS (DCI) m/z 350.12(M+H)⁺.

Example 24F1-Benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2-carboxamide

Ammonia in methanol (7N, 20 mL) was added to Example 24E (1.56 g, 4.46mmol) in a stainless steel autoclave, chilled to −75° C. followed by theaddition of anhydrous ammonia (5 mL). The reactor was scaled and heatedat 100° C. for 56 hours. The mixture was concentrated under reducedpressure and the residue was chromatographed on silica gel eluting with50-100% ethyl acetate in hexane to afford the title compound. ¹H NMR(300 MHz, CDCl₃) δ ppm 1.93 (m, 1H), 2.47 (m, 1H), 2.79 (m, 2H), 4.06(dd, J=5.94, 2.55 Hz, 1H), 4.40 (d, J=16.96 Hz, 1H), 4.86 (d, J=16.61Hz, 1H), 5.47 (br s, 1H), 6.16 (br s, 1H), 6.93 (m, 2H), 7.13 (d, J=7.12Hz, 1H), 7.21 (m, 2H), 7.31 (m, 3H). MS (DCI) m/z 335.10 (M+H)⁺.

Example 24G(1-Benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)methanamine

Lithium aluminum hydride (1.0M in THF, 9.7 mL, 9.7 mmol) was added toExample 24F (1.08 g, 3.24 mmol) in tetrahydrofuran (30 mL). The mixturestirred for 2 hours at ambient temperature then refluxed for 1 hour.After cooling to 0° C., was added sequentially water (0.8 mL),tetrahydrofuran (25 mL), 15% sodium hydroxide (0.8 mL) and water (1.6mL). The mixture was filtered, the solids were washed with ethyl acetate(200 mL), and the organic layer was dried over sodium sulfate, filtered,and concentrated under reduced pressure to afford the title compound. ¹HNMR (300 MHz, CDCl₃) δ ppm 1.92 (tt, J=12.76, 5.21 Hz, 1H), 2.14 (m,1H), 2.81 (m, 4H), 3.40 (td, J=8.31, 4.75 Hz, 1H), 4.62 (q, J=15.60 Hz,2H), 6.69 (s, 1H), 6.81 (d, J=7.80 Hz, 1H), 7.07 (d, J=7.12 Hz, 1H),7.24 (m, 2H), 7.29 (m, 2H). MS (DCI) m/z 321.08 (M+H)⁺.

Example 24H1-((1-Benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)methyl)-3-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)urea

To di(N-succinimidyl)carbonate (870 mg, 3.40 mmol) in acetonitrile (5mL) was added Example 1G (898 mg, 3.24 mmol) in acetonitrile (10 mL) andpyridine (0.28 mL, 3.40 mmol) and the mixture was stirred for 15 minutesat ambient temperature. Example 24G (1.09 g) dissolved in acetonitrile(15 mL) and diisopropylethylamine (1.7 mL, 9.7 mmol) were added and themixture stirred for 30 minutes. The mixture was concentrated underreduced pressure and the residue was chromatographed on silica geleluting with 0-30% ethyl acetate in hexane to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.08 (q, J=3.05 Hz, 6H), 0.86 (s, 9H),1.64 (m, 1H), 1.82 (m, 2H), 2.05 (m, 1H), 2.40 (dd, J=16.95, 7.46 Hz,1H), 2.77 (m, 4H), 2.94 (m, 1H), 3.57 (m, 1H), 4.10 (m, 1H), 4.67 (q,J=15.60 Hz, 2H), 6.52 (s, 1H), 6.68 (m, 1H), 6.74 (d, J=7.46 Hz, 2H),6.98 (t, J=7.80 Hz, 1H), 7.14 (d, J=7.80 Hz, 1H), 7.23 (m, 3H), 7.29 (m,2H), 7.46 (dd, J=7.12, 5.76 Hz, 1H), 7.58 (s, 1H). MS (ESI) m/z 624.46(M+H)⁺.

Example 241N-{[1-Benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl]methyl}-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

Example 24H (831 mg, 1.33 mmol) was dissolved in tetrahydrofuran (20mL), and tetrabutylammonium fluoride (1.0M in THF, 2.7 mL, 2.7 mmol) wasadded, and the mixture stirred overnight at ambient temperature. Themixture was concentrated under reduced pressure and the residue waschromatographed on silica gel eluting with 0-10% methanol in ethylacetate. The residue was dissolved in ethyl acetate (200 mL), and theorganic layer was washed with water (200 mL), brine, dried over sodiumsulfate, filtered, concentrate under reduced pressure, and vacuum driedovernight to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.58 (m, 1H), 1.85 (m, 2H), 2.06 (m, 1H), 2.34 (dd, J=16.62, 7.80 Hz,1H), 2.78 (m, 4H), 2.94 (m, 1H), 3.16 (m, 1H), 3.56 (m, 1H), 3.91 (m,1H), 4.69 (q, J=15.71 Hz, 2H), 4.85 (d, J=4.07 Hz, 1H), 6.53 (s, 1H),6.75 (m, 3H), 6.97 (t, J=7.80 Hz, 1H), 7.15 (d, J=7.80 Hz, 1H), 7.23 (m,3H), 7.32 (m, 2H), 7.58 (m, 2H). MS (ESI) m/z 510.33 (M+H)⁺. Calcd forC₂₉H₃₀F₃N₃O₂.0.37 EtOAc: C, 67.52; H, 6.13; N, 7.75. Found: C, 67.45; H,6.21; N, 7.91.

Example 25N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl]methyl}ureaExample 25A Methyl1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

Example 24D (1.31 g, 5.0 mmol), iodomethane (0.33 mL, 5.25 mmol) andpotassium carbonate (691 mg, 5.0 mmol) in dimethylformamide (8 mL) wereheated in a microwave at 120° C. for 1 hour. Ethyl acetate (200 mL) wasadded and the separated organic layer was washed with saturated sodiumbicarbonate (200 mL), brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford the title compound. ¹H NMR(300 MHz, CDCl₃) δ ppm 2.11 (m, 1H), 2.31 (m, 1H), 2.72 (m, 2H), 2.99(s, 3H), 3.72 (s, 3H), 4.08 (dd, J=5.76, 3.39 Hz, 1H), 6.79 (s, 1H),6.86 (d, J=7.80 Hz, 1H), 7.01 (d, J=7.80 Hz, 1H). MS (DCI) m/z 274.05(M+H)⁺.

Example 25B1-Methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-2-carboxamide

Ammonia in methanol (7M, 15 mL) was added to Example 25A (1.15 g, 4.22mmol) in a stainless steel autoclave and the mixture was cooled to −75°C. Anhydrous ammonia (10 mL) was added and the reactor was sealed andheated at 100° C. for 48 hours. The mixture was concentrated underreduced pressure and the residue was chromatographed on silica geleluting with 50-100% ethyl acetate in hexane to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.90 (m, 1H), 2.40 (dq, J=13.23,3.73 Hz, 1H), 2.73 (m, 2H), 3.06 (s, 3H), 3.89 (dd, J=6.10, 3.05 Hz,1H), 5.49 (br s, 1H), 6.13 (br s, 1H), 6.88 (s, 1H), 6.95 (d, J=7.80 Hz,1H), 7.09 (d, J=7.80 Hz, 1H). MS (DCI) m/z 259.07 (M+H)⁺.

Example 25C(1-Methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)methanamine

Lithium aluminum hydride (1.0M in THF, 8.1 mL, 8.1 mmol) was added toExample 25B (697 mg, 2.7 mmol) suspended in tetrahydrofuran (20 mL). Themixture stirred for 1 hour at ambient temperature then refluxed for 1hour. The mixture was cooled to 0° C. followed by the sequentialaddition of water (0.7 mL), tetrahydrofuran (20 mL), 15% sodiumhydroxide (0.7 mL) and water (1.4 mL). The mixture was filtered, thesolids were rinsed with ethyl acetate (200 mL) and the filtrate wasdried over sodium sulfate, filtered, and concentrated under reducedpressure to afford the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm1.85 (m, 1H), 2.06 (m, 1H), 2.74 (m, 3H), 2.91 (dd, J=13.05, 4.92 Hz,1H), 3.03 (s, 3H), 3.28 (m, 1H), 6.72 (s, 1H), 6.82 (d, J=7.46 Hz, 1H),7.02 (d, J=7.80 Hz, 1H). MS (DCI) m/z 245.06 (M+H)⁺.

Example 25DN-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl]methyl}urea

To di(N-succinimidyl)carbonate (417 mg, 1.63 mmol) in acetonitrile (5mL) was added Example 1G (430 mg, 1.55 mmol) in acetonitrile (5 mL) andpyridine (0.13 mL, 1.63 mmol) and the mixture stirred for 15 minutes atambient temperature. Example 25C (379 mg, 1.55 mmol) dissolved inacetonitrile (10 mL) and diisopropylethylamine (0.81 mL, 4.65 mmol) wereadded and the mixture stirred for 30 minutes. The mixture wasconcentrated under reduced pressure and the residue was chromatographedon silica gel eluting with 0-35% ethyl acetate in hexane, to afford1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-((1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)methyl)urea.The intermediate was dissolved in tetrahydrofuran (20 mL),tetrabutylammonium fluoride (1.0M in THF, 2.5 mL, 2.5 mmol) was added,and the mixture stirred overnight at ambient temperature. The mixturewas concentrated under reduced pressure and the residue waschromatographed on silica gel eluting with 0-10% methanol in ethylacetate. The solid was suspended in methanol (5 mL), sonicated, andwater (150 mL) was added. The sonication was repeated, the solids werecollected by filtration and rinsed with water, and freeze-dried toprovide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.58 (m,1H), 1.70 (m, 1H), 1.86 (m, 1H), 1.96 (m, 1H), 2.33 (dd, J=16.61, 7.80Hz, 1H), 2.78 (m, 5H), 3.00 (s, 3H), 3.06 (m, 1H), 3.41 (m, 1H), 3.91(m, 1H), 4.86 (d, J=4.07 Hz, 1H), 6.70 (m, 3H), 6.80 (d, J=7.46 Hz, 1H),6.98 (t, J=7.80 Hz, 1H), 7.11 (d, J=7.80 Hz, 1H), 7.56 (s, 1H), 7.61 (d,J=8.14 Hz, 1H). MS (ESI) m/z 434.22 (M+H)¹. Calcd for C₂₃H₂₆F₃N₃O₂: C,63.73; H, 6.05; N, 9.69. Found: C, 63.66; H, 5.97; N, 9.54.

Example 26N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{[7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl]methyl}ureaExample 26A1-(7-(tert-Butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-((7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)methyl)urea

Example 24H (780 mg, 1.25 mmol) was added to a mixture of ethanol (40mL) and 20% palladium hydroxide on carbon (190 mg) in a Parr shaker. Theglass reactor was sealed and flushed with nitrogen, and pressurized withhydrogen (60 psi). The mixture was shaken at ambient temperature for 18hours, filtered and concentrated under reduced pressure the filtrate toprovide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.08 (m,6H), 0.86 (s, 9H), 1.61 (m, 2H), 1.84 (m, 2H), 2.39 (dd, J=16.95, 7.46Hz, 1H), 2.75 (m, 5H), 3.08 (m, 1H), 4.11 (m, 1H), 6.21 (s, 1H), 6.71(m, 4H), 6.98 (m, 2H), 7.57 (m, 2H). MS (ESI) m/z 534.41 (M+H)⁺.

Example 26BN-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{[7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl]methyl}urea

To Example 26A (650 mg, 1.22 mmol) in tetrahydrofuran (20 mL) was addedtetrabutylammonium fluoride (1.0M in THF, 2.44 mL, 2.44 mmol) and themixture stirred overnight at ambient temperature. The mixture wasconcentrated under reduced pressure and chromatographed on silica geleluting with 0-to-10% methanol in ethyl acetate to afford a white solid.The residue was dissolved in methanol (10 mL) and water (150 mL). Themixture was sonicated and filtered. The solid was freeze-dried overnightto obtain the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.59 (m,2H), 1.86 (m, 2H), 2.33 (dd, J=16.45, 7.63 Hz, 1H), 2.76 (m, 5H), 3.08(m, 1H), 3.36 (m, 2H), 3.91 (m, 1H), 4.85 (dd, J=4.24, 2.20 Hz, 1H),6.23 (s, 1H), 6.70 (d, J=7.80 Hz, 2H), 6.78 (m, 2H), 6.98 (t, J=7.80 Hz,1H), 7.04 (d, J=7.80 Hz, 1H), 7.59 (s, 1H), 7.65 (d, J=7.80 Hz, 1H). MS(ESI) m/z 420.20 (M+H)⁺. Calcd for C₂₂H₂₄F₃N₃O₂.0.06 H₂O: C, 62.84; H,5.78; N, 9.99. Found: C, 62.85; H, 5.73; N, 9.93.

Example 27N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[(1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl]-ureaExample 27A Ethyl 1-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylate

Example 23B (2.46 g, 12.0 mmol), iodomethane (1.12 mL, 18.0 mmol) andpotassium carbonate (1.66 g, 12.0 mmol) in dimethylformamide (12 mL)were stirred overnight at ambient temperature. To the mixture was addedethyl acetate (200 mL). The separated organic solution was washed withwater (2×200 mL), brine (1×), dried over sodium sulfate, filtered andconcentrate under reduced pressure. The residue was chromatographed onsilica gel eluting with 0-to-20% ethyl acetate in hexane to provide thetitle compound. Obtained 2.21 g (84% yield) of Example 27A as acolorless liquid. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.24 (t, J=7.12 Hz, 3H),2.12 (m, 1H), 2.29 (dq, J=13.18, 4.31 Hz, 1H), 2.68 (d, J=4.41 Hz, 1H),2.71 (m, 1H), 2.95 (s, 3H), 4.01 (dd, J=5.08, 3.73 Hz, 1H), 4.17 (dq,J=8.14, 7.12 Hz, 2H), 6.63 (m, 2H), 6.94 (d, J=7.46 Hz, 1H), 7.10 (t,J=7.80 Hz, 1H). MS (DCI) m/z 220.10 (M+H)⁺.

Example 27B 1-Methyl-1,2,3,4-tetrahydroquinoline-2-carboxamide

Added 7N ammonia in methanol (40 mL) to Example 27A (2.10 g, 9.59 mmol)in a stainless steel autoclave chilled to −75° C. followed by theaddition of anhydrous ammonia (20 mL). The reactor was sealed and heatedat 100° C. for 48 hours. The mixture was concentrated under reducedpressure to a brown solid which was chromatographed on silica geleluting with 50-to-100% ethyl acetate in hexane to provide the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.82 (m, 1H), 2.10 (m, 1H),2.56 (m, 2H), 2.84 (s, 3H), 3.79 (dd, J=5.42, 3.73 Hz, 1H), 6.51 (td,J=7.29, 1.02 Hz, 1H), 6.57 (d, J=8.14 Hz, 1H), 6.87 (dd, J=7.12, 1.36Hz, 1H), 7.01 (t, J=7.80 Hz, 1H), 7.08 (s, 1H), 7.23 (s, 1H). MS (DCI)m/z 191.09 (M+H)⁺.

Example 27C (1-Methyl-1,2,3,4-tetrahydroquinolin-2-yl)methanamine

Lithium aluminum hydride (1.0M in THF, 18.9 mL, 18.9 mmol) was added toExample 27B (1.20 g, 6.3 mmol) in tetrahydrofuran (30 mL). The mixturewas stirred for 1.5 hours at ambient temperature then refluxed for 1hour. The mixture was chilled to 0° C., followed by the sequentialaddition of water (1.6 mL), tetrahydrofuran (50 mL), 15% sodiumhydroxide (1.6 mL) and water (3.2 mL). The mixture was filtered and thesolids were rinsed with ethyl acetate (200 mL). The combined organicsolution was dried with sodium sulfate and concentrated under reducedpressure to provide the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm1.87 (m, 1H), 2.03 (m, 1H), 2.72 (m, 3H), 2.89 (dd, J=12.88, 4.74 Hz,1H), 2.99 (s, 3H), 3.23 (m, 1H), 6.57 (d, J=8.14 Hz, 1H), 6.59 (t,J=7.12 Hz, 1H), 6.96 (d, J=7.12 Hz, 1H), 7.09 (t, J=7.80 Hz, 1H). MS(DCI) m/z 177.10 (M+H)⁺.

Example 27DN-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[(1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl]-urea

To di(N-succinimidyl)carbonate (538 mg, 2.1 mmol) in acetonitrile (5 mL)was added Example 1G (555 mg, 2.0 mmol) in acetonitrile (5 mL) andpyridine (0.17 mL, 2.1 mmol) and the mixture was stirred for 15 minutesat ambient temperature. Example 27C (353 mg, 2.0 mmol) in acetonitrile(10 mL) and diisopropylethylamine (1.05 mL, 6.0 mmol) were added and themixture was stirred for 30 minutes. The mixture was concentrated underreduced pressure and chromatographed on silica gel eluting with 0-to-40%ethyl acetate in hexane to provide 780 mg of1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-((1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl)ureaas a white foam. The intermediate was dissolved in tetrahydrofuran (20mL) followed by the addition of tetrabutylammonium fluoride (1.0M inTHF, 3.25 mL, 3.25 mmol) and the mixture was stirred overnight atambient temperature. The mixture was concentrated under reduced pressureand chromatographed on silica gel eluting with 0-to-10% methanol inethyl acetate to afford a white solid. The residue was suspended inmethanol (15 mL), sonicated followed by the addition of water (250 mL),repeated sonication, the solids were collected by filtration, rinsedwith water, and freeze-dried the wet cake overnight to provide the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.58 (m, 1H), 1.71 (m, 1H),1.90 (m, 2H), 2.33 (dd, J=16.28, 8.14 Hz, 1H), 2.60 (m, 1H), 2.78 (m,4H), 2.94 (s, 3H), 3.03 (m, 1H), 3.92 (br s, 1H), 4.86 (d, J=4.07 Hz,1H), 6.50 (m, 2H), 6.71 (m, 2H), 6.91 (d, J=7.12 Hz, 1H), 6.98 (m, 2H),7.55 (s, 1H), 7.63 (d, J=8.14 Hz, 1H). MS (ESI) m/z 366.20 (M+H)⁺. Calcdfor C₂₂H₂₇N₃O₂: C, 72.30; H, 7.45; N, 11.50. Found: C, 72.37; H, 7.50;N, 11.46.

Example 28N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{(3R)-3-[4-(trifluoromethyl)phenyl]cyclohexyl}ureaExample 28A (R)-3-(4-(trifluoromethyl)phenyl)cyclohexanone

To a 40 ml microwave flask containing dioxane/H₂O (10/1) (22 mL) wasadded cyclohexen-1-one (1.35 g, 14.0 mmol),acetylacetonatobis(ethylene)rhodium(I) (0.36 g, 1.40 mmol),R-2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl (0.88 g, 1.40 mmol) and4-(trifluoromethyl)-phenylboronic acid (5.0 g, 28.0 mmol). The mixturewas heated in the microwave (Personal Chemistry) at 100° C. for 20minutes. The material was transferred to a separatory funnel andextracted with ethyl acetate (150 mL). The resulting organic layer waswashed with NaHCO₃ (75 mL), dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The mixture was purified on SiO₂ (hexane/ethylacetate 4/1) to provide the title compound. [α]_(D)=⁺13.62 c=1.0(CH₃OH). ¹H NMR (CD₃OD, 300 MHz); δ 1.72-2.20 (m, 5H), 2.35-2.73 (m,3H), 3.06-3.15 (m, 1H), 7.40-7.42 (m, 2H), 7.46-7.63 (m, 2H). MS (+ESI)m/z 242 (M+NH₄—H₂O)⁺.

Example 28B (R)-3-(4-(trifluoromethyl)phenyl)cyclohexanone O-methyloxime

To a flask containing Example 28A (1.97 g, 8.60 mmol) was added pyridine(10 mL) followed by N-methoxyamine hydrochloride (0.81 g, 9.60 mmol) andthe mixture was stirred at room temperature overnight. The mixture wasconcentrated under reduced pressure, taken up in ethyl acetate, washedwith sat NaHCO₃, dried (Na₂SO₄), filtered and concentrated under reducedpressure. The residue was purified on SiO₂ (hexane/ethyl acetate 4/1) toprovide the title compound. ¹H NMR (CD₃OD, 300 MHz); δ 1.48-1.89 (m,2H), 1.92-2.52 (m, 5H), 2.75-2.87 (m, 1H), 3.22-3.35 (m, 1H), 3.79 (d,J=1.70 Hz, 3H), 7.46 (d, J=8.14 Hz, 2H), 7.60 (d, J=8.48 Hz, 2H). MS(DCI) m/z 272 (M+H)⁺.

Example 28C (3R)-3-(4-(trifluoromethyl)phenyl)cyclohexanamine

To a flask containing Example 28B (1.80 g, 6.90 mmol) was addedsaturated NH₃/CH₃OH (50 mL), RaNi (20%, 5.0 eq by weight) and subjectedto an atmosphere of hydrogen gas (60 psi). The mixture was stirred atroom temperature for 3 hours, filtered and washed with 50 mL ofmethanol. The solution was concentrated under reduced pressure and theresidue was purified on SiO₂ (hexane/ethyl acetate 1/1) to afford thetitle compound. ¹H NMR (CD₃OD, 300 MHz); δ 1.45-1.86 (m, 3H), 1.95-2.55(m, 5H), 2.80-2.88 (m, 1H), 3.20-3.35 (m, 1H), 7.45 (d, J=8.1 Hz, 2H),7.60 (d, J=8.4 Hz, 2H). MS (DCI) m/z 244 (M+H)⁺.

Example 28D1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-((3R)-3-(4-(trifluoromethyl)phenyl)cyclohexyl)urea

In a 250 mL round bottom flask containing acetonitrile (20 mL) was addedExample 1G (0.80 g, 2.90 mmol) followed by di(succinimidyl)carbonate(0.24 g, 3.0 mmol) (Fluka) and pyridine (0.25 mL). The mixture wasstirred at room temperature for 30 minutes. Example 28C (0.70 g, 2.90mmol) was added as a solution in acetonitrile (10 mL) anddisopropylethylamine (1.60 mL, 9.10 mmol) to the mixture and allowed tostir at room temperature overnight. The mixture was concentrated underreduced pressure. The material was purified on SiO₂ (hexane/ethylacetate 4/1 to 1/1) to provide the title compound. ¹H NMR (DMSO, 300MHz); δ 0.86 (s, 9H), 1.18-2.18 (m, 15H), 2.45-2.58 (m, 1H), 2.71-2.98(m, 4H), 3.65-3.76 (m, 1H), 4.05-4.18 (m, 2H), 6.83-6.88 (m, 1H),7.01-7.06 (m, 1H), 7.26 (d, J=7.80 Hz, 1H), 7.36-7.43 (m, 2H), 7.55-7.58(m, 2H). MS (DCI) m/z 547 (M+H)⁺.

Example 28E1-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-3-((3R)-3-(4-(trifluoromethyl)phenyl)cyclohexyl)urea

To a round bottom flask containing Example 28D (1.56 g, 2.90 mmol) wasadded THF (30 mL) followed by tetrabutylammoniumfluoride 1M in THF (5.70mL) and the mixture was stirred at room temperature overnight. Themixture was concentrated under reduced pressure. The material waspurified on SiO₂ (hexane/ethyl acetate 1/6) to provide the titlecompound. ¹H NMR (DMSO, 300 MHz); δ 1.07-2.07 (m, 10H), 2.27-2.40 (m,1H), 2.63-2.87 (m, 4H), 3.54-3.64 (m, 0.5H), 3.85-3.97 (m, 0.5H),4.83-4.90 (m, 1H), 6.57 (d, J=7.12 Hz, 1H), 6.68 (d, J=7.12 Hz, 1H),6.93-6.99 (m, 1H), 7.41 (s, 1H), 7.47-7.51 (m, 2H), 7.63-7.66 (m, 3H).MS (DCI) m/z 433 (M+H)⁺. Calc for C₂₄H₂₇N₂O₂F₃: C, 71.29; H, 8.03; N,10.39. Found: C, 71.18; H, 8.07; N, 10.02.

Example 29N-{(3S)-3-[4-(dimethylamino)phenyl]cyclopentyl}-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ureaExample 29A (S)-3-(4-(dimethylamino)phenyl)cyclopentanone

The title compound was prepared using the procedure as described inExample 28A, substituting 2-cyclopenten-1-one for cyclohexen-1-one,S-BINAP and 4-(dimethylamino)-phenylboronic acid for4-(tertbutyl)-phenylboronic acid. The mixture was purified on SiO₂(hexane/ethyl acetate 4/1) to provide the title compound. [α]_(D)=⁻22.31c=1.0 (CH₃OH). ¹H NMR (CD₃OD, 300 MHz); δ 1.85-2.01 (m, 1H), 2.21-2.40(m, 4H), 2.42-2.50 (m, 1H), 2.88 (s, 6H), 3.29-3.39 (m, 1H), 6.78-6.81(m, 2H), 7.11-7.21 (m, 2H). MS (DCI) m/z 204 (M+H)⁺.

Example 29B (S)-3-(4-(dimethylamino)phenyl)cyclopentanone O-methyl oxime

The title compound was prepared using the procedure as described inExample 28B, substituting Example 29A for Example 28A. Purified on SiO₂(hexane/ethyl acetate 1/1) to provide the title compound. ¹H NMR (CD₃OD,300 MHz); δ 1.85-2.00 (m, 1H), 2.20-2.45 (m, 4H), 2.48-2.52 (m, 1H),2.90 (s, 6H), 3.30-3.40 (m, 1H), 3.90 (s, 3H), 6.75-6.80 (m, 2H),7.10-7.20 (m, 2H). MS (DCI) m/z 219 (M+H)⁺.

Example 29C 4-((1S)-3-aminocyclopentyl)-N,N-dimethylaniline

The title compound was prepared using the procedure as described inExample 28C, except for substituting Example 29B for Example 28B.Purified on SiO₂ (hexane/ethyl acetate 1/4) to provide the titlecompound. ¹H NMR (CD₃OD, 300 MHz); δ 1.33-1.65 (m, 2H), 1.68-2.32 (m,4H), 2.86 (s, 6H), 3.08-3.54 (m, 2H), 6.70-6.84 (m, 2H), 7.05-7.13 (m,2H). MS (DCI) m/z 205 (M+H)¹.

Example 29D1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-((3S)-3-(4-(dimethylamine)phenyl)cyclopentyl)urea

In a 250 mL round bottom flask containing acetonitrile (20 mL) was addedExample 1G (0.80 g, 2.90 mmol) followed by di(succinimidyl)carbonate(0.24 g, 3.0 mmol) (Fluka) and pyridine (0.25 mL). The mixture wasstirred at room temperature for 30 minutes. Example 29C (0.70 g, 2.90mmol) was added as a solution in acetonitrile (10 mL) anddisopropylethylamine (1.60 mL, 9.10 mmol) to the mixture and allowed tostir at room temperature overnight. The mixture was concentrated underreduced pressure. The material was purified on SiO₂ (hexane/ethylacetate 4/1 to 1/1) to provide the title compound. ¹H NMR (DMSO, 300MHz); δ 0.87 (s, 9H), 1.31-1.70 (m, 3H), 1.79-2.10 (m, 4H), 2.26-2.42(m, 2H), 2.65-3.11 (m, 10H), 3.31 (s, 6H), 3.98-4.16 (m, 2H), 6.65-6.71(m, 4H), 6.95 (t, J=7.80, 1H), 7.03-7.10 (m, 2H), 7.37 (d, J=7.80 Hz,1H), 7.54-7.64 (m, 1H). MS (DCI) m/z 508 (M+H)⁺.

Example 29E1-((3S)-3-(4-(dimethylamino)phenyl)cyclopentyl)-3-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea

To a round bottom flask containing Example 29D (1.0 g, 2.0 mmol) wasadded THF (20 mL) followed by tetrabutylammoniumfluoride 1M in THF (4.0mL) and the mixture was stirred at room temperature overnight. Themixture was concentrated under reduced pressure and the material waspurified on SiO₂ (ethyl acetate/10% methanol) to provide the titlecompound. ¹H NMR (DMSO, 300 MHz); δ 1.31-1.64 (m, 4H), 1.79-2.36 (m,7H), 2.61-2.81 (m, 8H), 2.84-3.12 (m, 1H), 3.92-4.07 (m, 1H), 6.66-6.79(m, 4H), 6.97 (t, J=7.12 Hz, 1H), 7.06-7.10 (m, 2H), 7.36 (d, J=6.80 Hz,1H), 7.69 (t, J=6.80 Hz, 1H). MS (DCI) m/z 394 (M+H)⁺. Calc forC₂₄H₃₁N₃O₂: C, 71.29; H, 8.03; N, 10.39. Found: C, 71.18; H, 8.07; N,10.02.

Pharmaceutical Compositions

The application also provides pharmaceutical compositions comprising atherapeutically effective amount of a compound of formula (I) incombination with a pharmaceutically acceptable carrier. The compositionscomprise compounds of the application formulated together with one ormore non-toxic pharmaceutically acceptable carriers. The pharmaceuticalcompositions can be formulated for oral administration in solid orliquid form, for parenteral injection or for rectal administration.

The term “pharmaceutically acceptable carrier,” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols; such a propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of one skilledin the art of formulations.

The pharmaceutical compositions of this application can be administeredto humans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administration,including intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous, intraarticular injection and infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like, and suitable mixturesthereof), vegetable oils (such as olive oil) and injectable organicesters such as ethyl oleate, or suitable mixtures thereof. Suitablefluidity of the composition may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms can be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It also can bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form can be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug can depend upon its rateof dissolution, which, in turn, may depend upon crystal size andcrystalline form. Alternatively, a parenterally administered drug formcan be administered by dissolving or suspending the drug in an oilvehicle.

Suspensions, in addition to the active compounds, can contain suspendingagents, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds of theapplication can be incorporated into slow-release or targeted-deliverysystems such as polymer matrices, liposomes, and microspheres. They maybe sterilized, for example, by filtration through a bacteria-retainingfilter or by incorporation of sterilizing agents in the form of sterilesolid compositions, which may be dissolved in sterile water or someother sterile injectable medium immediately before use.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations also are prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation also can be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, one or morecompounds of the application is mixed with at least one inertpharmaceutically acceptable carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and salicylic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay; and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using lactose or milk sugar aswell as high molecular weight polyethylene glycols.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well-known in the pharmaceutical formulatingart. They can optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of materials useful for delaying release of the activeagent can include polymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisapplication with suitable non-irritating carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Dosage forms for topical or transdermal administration of a compound ofthis application include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. A desired compound ofthe application is admixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives orbuffers as may be required. Ophthalmic formulation, eardrops, eyeointments, powders and solutions are also contemplated as being withinthe scope of this application. The ointments, pastes, creams and gelsmay contain, in addition to an active compound of this application,animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth,cellulose derivatives, polyethylene glycols, silicones, bentonites,silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisapplication, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Compounds of the application also can be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the application, stabilizers, preservatives, and the like.The preferred lipids are the natural and synthetic phospholipids andphosphatidylcholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y., (1976), p 33 et seq.

Dosage forms for topical administration of a compound of thisapplication include powders, sprays, ointments and inhalants. The activecompound is mixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives, buffers or propellants.Ophthalmic formulations, eye ointments, powders and solutions are alsocontemplated as being within the scope of this application. Aqueousliquid compositions of the application also are particularly useful.

The compounds of the application can be used in the form ofpharmaceutically acceptable salts, esters, or amides derived frominorganic or organic acids. The term “pharmaceutically acceptable salts,esters and amides,” as used herein, include salts, zwitterions, estersand amides of compounds of formula (I) which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, are commensurate with a reasonable benefit/riskratio, and are effective for their intended use.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theapplication or separately by reacting a free base function with asuitable organic acid.

Representative acid addition salts include, but are not limited toacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates such as dimethyl,diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkylhalides such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

Examples of acids which can be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acidand such organic acids as oxalic acid, maleic acid, succinic acid, andcitric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this application by reacting acarboxylic acid-containing moiety with a suitable base such as thehydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas lithium, sodium, potassium, calcium, magnesium, and aluminum salts,and the like, and nontoxic quaternary ammonia and amine cationsincluding ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,ethylamine and the such as. Other representative organic amines usefulfor the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, and piperazine.

The term “pharmaceutically acceptable ester,” as used herein, refers toesters of compounds of the application which hydrolyze in vivo andinclude those that break down readily in the human body to leave theparent compound or a salt thereof. Examples of pharmaceuticallyacceptable, non-toxic esters of the application include C₁-to-C₆ alkylesters and C₅-to-C₇ cycloalkyl esters, although C₁-to-C₄ alkyl estersare preferred. Esters of the compounds of formula (I) can be preparedaccording to conventional methods. Pharmaceutically acceptable esterscan be appended onto hydroxy groups by reaction of the compound thatcontains the hydroxy group with acid and an alkylcarboxylic acid such asacetic acid, or with acid and an arylcarboxylic acid such as benzoicacid. In the case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine and an alkyl halide, alkyl trifilate, forexample with methyl iodide, benzyl iodide, cyclopentyl iodide. They alsocan be prepared by reaction of the compound with an acid such ashydrochloric acid and an alkylcarboxylic acid such as acetic acid, orwith acid and an arylcarboxylic acid such as benzoic acid.

The term “pharmaceutically acceptable amide,” as used herein, refers tonon-toxic amides of the application derived from ammonia, primaryC₁-to-C₆ alkyl amines and secondary C₁-to-C₆ dialkyl amines. In the caseof secondary amines, the amine can also be in the form of a 5- or6-membered heterocycle containing one nitrogen atom. Amides derived fromammonia, C₁-to-C₃ alkyl primary amides and C₁-to-C₂ dialkyl secondaryamides are preferred. Amides of the compounds of formula (I) can beprepared according to conventional methods. Pharmaceutically acceptableamides can be prepared from compounds containing primary or secondaryamine groups by reaction of the compound that contains the amino groupwith an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide.In the case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine,for example with methylamine, diethylamine, piperidine. They also can beprepared by reaction of the compound with an acid such as sulfuric acidand an alkylcarboxylic acid such as acetic acid, or with acid and anarylcarboxylic acid such as benzoic acid under dehydrating conditions aswith molecular sieves added. The composition can contain a compound ofthe application in the form of a pharmaceutically acceptable prodrug.

The term “pharmaceutically acceptable prodrug” or “prodrug,” as usedherein, represents those prodrugs of the compounds of the applicationwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use.Prodrugs of the application can be rapidly transformed in vivo to aparent compound of formula (I), for example, by hydrolysis in blood. Athorough discussion is provided in T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and inEdward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press (1987).

The application contemplates pharmaceutically active compounds eitherchemically synthesized or formed by in vivo biotransformation tocompounds of formula (I).

Biological Activity

In Vitro Data—Determination of Inhibition Potencies Dulbecco's modifiedEagle medium (D-MEM)(with 4.5 mg/mL glucose) and fetal bovine serum wereobtained from Hyclone Laboratories, Inc. (Logan, Utah). Dulbecco'sphosphate-buffered saline (D-PBS) (with 1 mg/mL glucose and 3.6 mg/l Napyruvate) (without phenol red), L-glutamine, hygromycin B, andLipofectamine™ were obtained from Life Technologies (Grand Island,N.Y.). G418 sulfate was obtained from Calbiochem-Novabiochem Corp. (SanDiego, Calif.). Capsaicin (8-methyl-N-vanillyl-6-nonenamide) wasobtained from Sigma-Aldrich, Co. (St. Louis, Mo.). Fluo-4 AM(N-[4-[6-[(acetyloxy)methoxy]-2,7-difluoro-3-oxo-3H-xanthen-9-yl]-2-[2-[2-[bis[2-[(acetyloxy)methoxy]-2-oxyethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-N-[2-[(acetyloxy)methoxy]-2-oxyethyl]-glycine,(acetyloxy)methyl ester) was purchased from Molecular Probes (Eugene,Oreg.).

The cDNAs for the human TRPV1 receptor were isolated by reversetranscriptase-polymerase chain reaction (RT-PCR) from human smallintestine poly A+RNA supplied by Clontech (Palo Alto, Calif.) usingprimers designed surrounding the initiation and termination codonsidentical to the published sequences (Hayes et al. Pain 88: 205-215,2000). The resulting cDNA PCR products were subcloned into pCIneomammalian expression vector (Promega) and fully sequenced usingfluorescent dye-terminator reagents (Prism, Perkin-Elmer AppliedBiosystems Division) and a Perkin-Elmer Applied Biosystems Model 373 DNAsequencer or Model 310 genetic analyzer. Expression plasmids encodingthe hTRPV1 cDNA were transfected individually into 1321N1 humanastrocytoma cells using Lipofectamine™. Forty-eight hours aftertransfection, the neomycin-resistant cells were selected with growthmedium containing 800 μg/mL Geneticin (Gibco BRL). Surviving individualcolonies were isolated and screened for TRPV1 receptor activity. Cellsexpressing recombinant homomeric TRPV1 receptors were maintained at 37°C. in D-MEM containing 4 mM L-glutamine, 300 μg/mL G418 (Cal-biochem)and 10% fetal bovine serum under a humidified 5% CO₂ atmosphere.

The functional activity of compounds at the TRPV1 receptor wasdetermined with a Ca²⁺ influx assay and measurement of intracellularCa²⁺ levels ([Ca²⁺]i). All compounds were tested over an 11-pointhalf-log concentration range. Compound solutions were prepared in D-PBS(4× final concentration), and diluted serially across 96-well v-bottomtissue culture plates using a Biomek 2000 robotic automation workstation(Beckman-Coulter, Inc., Fullerton, Calif.). A 0.2 μM solution of theTRPV1 agonist capsaicin was also prepared in D-PBS. The fluorescent Ca²⁺chelating dye fluo-4 was used as an indicator of the relative levels of[Ca²⁺]i in a 96-well format using a Fluorescence Imaging Plate Reader(FLIPR) (Molecular Devices, Sunnyvale, Calif.). Cells were grown toconfluency in 96-well black-walled tissue culture plates. Then, prior tothe assay, the cells were loaded with 100 μL per well of fluo-4 AM (2μM, in D-PBS) for 1-2 hours at 23° C. Washing of the cells was performedto remove extracellular fluo-4 AM (2×1 mL D-PBS per well), andafterward, the cells were placed in the reading chamber of the FLIPRinstrument. 50 μL of the compound solutions were added to the cells atthe 10 second time mark of the experimental run. Then, after a 3 minutetime delay, 50 μL of the capsaicin solution was added at the 190 secondtime mark (0.05 μM final concentration) (final volume=200 μL) tochallenge the TRPV1 receptor. Time length of the experimental run was240 seconds. Fluorescence readings were made at 1 to 5 second intervalsover the course of the experimental run. The peak increase in relativefluorescence units (minus baseline) was calculated from the 190 secondtime mark to the end of the experimental run, and expressed as apercentage of the 0.05 M capsaicin (control) response. Curve-fits of thedata were solved using a four-parameter logistic Hill equation inGraphPad Prism® (GraphPad Software, Inc., San Diego, Calif.), and IC₅₀values were calculated.

The compounds of the present application were found to be antagonists ofthe vanilloid receptor subtype 1 (TRPV1) receptor with IC_(50s) lowerthan 12 μM, preferably lower than 5 M, more preferably less than 1 μM,and most preferably less than 0.1 μM.

In Vivo Data—Determination of Antinociceptive Effect

Experiments were performed on 400 adult male 129J mice (JacksonLaboratories, Bar Harbor, Me.), weighing 20-25 g. Mice were kept in avivarium, maintained at 22° C., with a 12 hour alternating light-darkcycle with food and water available ad libitum. All experiments wereperformed during the light cycle. Animals were randomly divided intoseparate groups of 10 mice each. Each animal was used in one experimentonly and was sacrificed immediately following the completion of theexperiment. All animal handling and experimental procedures wereapproved by an IACUC Committee. The Complete Freund's Adjuvant-inducedThermal Hyperalgesia (CFA) assay described in Pircio et al., Eur JPharmacol. Vol. 31(2), pages 207-215 (1975). Chronic inflammatoryhyperalgesia was induced in one group of rats following the injection ofcomplete Freund's adjuvant (CFA, 50%, 150 μL) into the plantar surfaceof the right hindpaw 48 hours prior to testing. Thermal nociceptivethresholds were measured in three different groups of rats. The ED_(50s)were determined based on the oral administration.

The in vitro and in vivo data demonstrates that compounds of the presentapplication antagonize the TRPV1 receptor and are useful for treatingpain, bladder overactivity, and urinary incontinence.

Methods of Use

Compounds and compositions of the application are useful forameliorating or preventing disorders involving TRPV1 receptor activationsuch as, but not limited to pain, nociceptive pain, neuropathic pain,migraine, ostheoarthritis pain, chronic lower pain, allodynia, painassociated with inflammation, bladder overactivity, and urinaryincontinence as described by Nolano, M. et al., Pain, Vol. 81, pages135-145, (1999); Caterina, M. J. and Julius, D., Annu. Rev. Neurosci.Vol. 24, pages 487-517 (2001); Caterina, M. J. et al., Science Vol. 288pages 306-313 (2000); Caterina, M. J. et al., Nature Vol. 389, pages816-824 (1997); Fowler, C. Urology Vol. 55, pages 60-64 (2000); andDavis, J. et al., Nature Vol. 405, pages 183-187.

Compounds of the invention may be administered alone, or in combinationwith one or more other compounds of the invention, or in combination(i.e. co-administered) with one or more additional pharmaceuticalagents. For example, a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof, may be administered in combinationwith one or more nonsteroidal anti-inflammatory drug (NSAID) such as,but not limited to, aspirin, acetaminophen, diclofenac, diflusinal,etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen,indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid,meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen,olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine,sulindac, tolmetin and zomepirac. Combination therapy includesadministration of a single pharmaceutical dosage formulation containingone or more of the compounds of invention and one or more additionalpharmaceutical agents, as well as administration of the compounds of theinvention and each additional pharmaceutical agent, in its own separatepharmaceutical dosage formulation. For example, a compound of formula(I) and one or more additional pharmaceutical agents, may beadministered to the patient together, in a single oral dosagecomposition having a fixed ratio of each active ingredient, such as atablet or capsule; or each agent may be administered in separate oraldosage formulations.

Where separate dosage formulations are used, compounds of the inventionand one or more additional pharmaceutical agents may be administered atessentially the same time (e.g., concurrently) or at separatelystaggered times (e.g., sequentially).

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

Compounds of the invention can also be administered as a pharmaceuticalcomposition comprising the compounds of interest in combination with oneor more pharmaceutically acceptable carriers. The phrase“therapeutically effective amount” of the compound of the inventionmeans a sufficient amount of the compound to treat disorders, at areasonable benefit/risk ratio applicable to any medical treatment. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the invention will be decided by the attendingphysician within the scope of sound medical judgment. The specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed; and like factorswell-known in the medical arts. For example, it is well within the skillof the art to start doses of the compound at levels lower than requiredto achieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

What is claimed is:
 1. A compound of formula (I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein L₁ isa bond, alkylene, or cycloalkyl; Y₁ is —N(R_(b))— or —C(R_(8a)R_(8b))—;Y₂ is ═O, ═S or —N—CN; Y₃ is —N(R_(c))—; Ar₁ is aryl or heteroaryl whenL₁ is cycloalkyl; or Ar₁ is a monocyclic heterocycle fused to an aryl ora monocyclic heterocycle fused to a monocyclic heteroaryl when L₁ is abond or alkylene; wherein each Ar₁ is optionally substituted with 1, 2,3, 4, or 5 substituents as represented by R_(w), two R_(w) that areattached to the same carbon atom of the monocyclic heterocycle, togetherwith the carbon atom to which they are attached, optionally form amonocyclic cycloalkyl ring wherein said monocyclic cycloalkyl ring isoptionally substituted with 1, 2, or 3 substituents selected from thegroup consisting of oxo, alkyl, and haloalkyl; R₁ is hydrogen, hydroxyor alkoxy; R_(w), R₂, R₃, R₄, and R₅, are each independently hydrogen,alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano,cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl,haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl,nitro, R_(e)OS(O)₂—, R_(f)R_(g)N—, (R_(f)R_(g)N)alkyl,(R_(j)R_(k)N)carbonyl, (R_(j)R_(k)N)carbonylalkyl or(R_(j)R_(k)N)sulfonyl; R_(8a) is hydrogen or alkyl; R_(8b) is hydrogenor alkyl; or R_(8a) and R_(8b) taken together with the carbon atoms towhich they are attached, form a 3-6 membered cycloalkyl ring; R_(b) andR_(c) are each independently hydrogen or alkyl; R_(e) is alkyl,haloalkyl, aryl, or arylalkyl; R_(f) and R_(g), at each occurrence, areeach independently hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,arylalkyl, arylcarbonyl, carboxyalkyl, cycloalkylalkyl, haloalkyl,heteroarylalkyl, or heteroarylcarbonyl; or R_(f) and R_(g) takentogether with the nitrogen atom to which they are attached form aheterocyclic ring; and R_(j) and R_(k), at each occurrence, are eachindependently hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl,alkyl, alkylcarbonylalkyl, carboxyalkyl, cycloalkylalkyl, haloalkyl, orhydroxyalkyl.
 2. The compound according to claim 1 wherein Y₁ is—N(R_(b))—; Y₂ is O; and Y₃ is —N(R_(c))—.
 3. The compound according toclaim 2, wherein L₁ is cycloalkyl wherein the cycloalkyl is cyclopentylor cyclohexyl.
 4. The compound of claim 3, wherein Ar₁ is phenyl.
 5. Thecompound according to claim 4, wherein the phenyl is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents as represented by R^(w)and each R^(w) is independently alkoxy, alkyl, arylalkyl, halogen,haloalkyl, or R_(f)R_(g)N— wherein R_(f) and R_(g) are eachindependently hydrogen, alkyl, or haloalkyl.
 6. The compound accordingto claim 5, wherein R₁ is hydroxy; and R₂, R₃, R₄, and R₅ are hydrogen.7. The compound according to claim 2, wherein L₁ is a bond.
 8. Thecompound according to claim 7, wherein Ar₁ is a monocyclic heterocyclefused to a phenyl.
 9. The compound of claim 8, wherein R₁ is hydroxy; R₂is hydrogen, and Ar₁ is 3,4-dihydro-2H-chromen-3-yl.
 10. The compoundaccording to claim 9 wherein Ar₁ is optionally substituted with 1, 2, 3,4, or 5 substituents as represented by R_(w) and each R_(w) isindependently alkoxy, alkyl, arylalkyl, halogen, haloalkyl, orR_(f)R_(g)N— wherein R_(f) and R_(g) are each independently hydrogen,alkyl, or haloalkyl.
 11. The compound according to claim 8, wherein R₁is hydroxy; R₂ is hydrogen; and Ar₁ is 3,4-dihydro-2H-chromen-4-yl. 12.The compound according to claim 11 wherein Ar₁ is optionally substitutedwith 1, 2, 3, 4, or 5 substituents as represented by R_(w) and eachR_(w) is independently alkoxy, alkyl, arylalkyl, halogen, haloalkyl, orR_(f)R_(g)N— wherein R_(f) and R_(g) are each independently hydrogen,alkyl, or haloalkyl.
 13. The compound according to claim 7, wherein Ar₁is a monocyclic heterocycle fused to a bicyclic aryl; R₁ is hydroxy; andR₂ is hydrogen.
 14. The compound according to claim 13 wherein Ar₁ is3,4,7,8,9,10-hexahydro-2H-benzo[h]chromen-4-yl.
 15. The compoundaccording to claim 8, wherein R₁ is hydroxy; R₂ is hydrogen; and Ar₁ is1,2,3,4-tetrahydroquinolin-4-yl.
 16. The compound according to claim 15wherein Ar₁ is optionally substituted with 1, 2, 3, 4, or 5 substituentsas represented by R_(w) and each R_(w) is independently alkoxy, alkyl,arylalkyl, halogen, haloalkyl, or R_(f)R_(g)N— wherein R_(f) and R_(g)are each independently hydrogen, alkyl, or haloalkyl.
 17. The compoundaccording to claim 8, wherein R₁ is hydroxy; R₂ is hydrogen; and Ar₁ is1,2,3,4-tetrahydroquinolin-3-yl.
 18. The compound according to claim 17wherein Ar₁ is optionally substituted with 1, 2, 3, 4, or 5 substituentsas represented by R_(w) and each R_(w) is independently alkoxy, alkyl,arylalkyl, halogen, haloalkyl, or R_(f)R_(g)N— wherein R_(f) and R_(g)are each independently hydrogen, alkyl, or haloalkyl.
 19. The compoundaccording to claim 2 wherein L₁ is alkylene.
 20. The compound accordingto claim 19, wherein Ar₁ is a monocyclic heterocycle fused to a phenyl.21. The compound according to claim 20, wherein R₁ is hydroxy; R₂ ishydrogen; and Ar₁ is 3,4-dihydro-2H-chromen-2-yl,3,4-dihydro-2H-chromen-3-yl, or 3,4-dihydro-2H-chromen-4-yl.
 22. Thecompound according to claim 21 wherein Ar₁ is optionally substitutedwith 1, 2, 3, 4, or 5 substituents as represented by R_(w) and eachR_(w) is independently alkoxy, alkyl, arylalkyl, halogen, haloalkyl, orR_(f)R_(g)N— wherein R_(f) and R_(g) are each independently hydrogen,alkyl, or haloalkyl.
 23. The compound according to claim 20, wherein R₁is hydroxy; R₂ is hydrogen; and Ar₁ is 1,2,3,4-tetrahydro-quinolin-2-yl,1,2,3,4-tetrahydro-quinolin-3-yl, or 1,2,3,4-tetrahydro-quinolin-4-yl.24. The compound according to claim 23 wherein Ar₁ is optionallysubstituted with 1, 2, 3, 4, or 5 substituents as represented by R_(w)and each R_(w) is independently alkoxy, alkyl, arylalkyl, halogen,haloalkyl, or R_(f)R_(g)N— wherein R_(f) and R_(g) are eachindependently hydrogen, alkyl, or haloalkyl.
 25. The compound accordingto claim 1 selected form the group consisting of:N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{(3R)-3-[4-(trifluoromethyl)phenyl]cyclohexyl}urea;N-{(3S)-3-[4-(dimethylamino)phenyl]cyclopentyl}-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-3,4-dihydro-2H-chromen-3-yl-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-(8-tert-butyl-3,4-dihydro-2H-chromen-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(7-methoxy-3,4-dihydro-2H-chromen-3-yl)urea;N-(6-chloro-3,4-dihydro-2H-chromen-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-(8-tert-butyl-3,4-dihydro-2H-chromen-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-3,4,7,8,9,10-hexahydro-2H-benzo[h]chromen-4-yl-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(6-methyl-3,4-dihydro-2H-chromen-4-yl)urea;N-[(4R)-3,4-dihydro-2H-chromen-4-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-(3,4-dihydro-2H-chromen-2-ylmethyl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-[(7-ethoxy-3,4-dihydro-2H-chromen-2-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[(6-methyl-3,4-dihydro-2H-chromen-2-yl)methyl]urea;N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[(8-isopropyl-3,4-dihydro-2H-chromen-2-yl)methyl]urea;N-(8-tert-butyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-(1-benzyl-1,2,3,4-tetrahydroquinolin-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-[1-benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)urea;N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]urea;N-(1-benzyl-1,2,3,4-tetrahydroquinolin-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-[1-benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)urea;N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]urea;N-[(1-benzyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-{[1-benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl]methyl}-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl]methyl}urea;N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{(3R)-3-[4-(trifluoromethyl)phenyl]cyclohexyl}urea;andN-{(3S)-3-[4-(dimethylamino)phenyl]cyclopentyl}-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea.26. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) according to claim 1, or apharmaceutically acceptable salt, ester, amide, or prodrug thereof. 27.The pharmaceutical composition according to claim 26 further including anon-toxic pharmaceutically acceptable carrier and diluent.
 28. A methodof treating a disorder, wherein the disorder is ameliorated byinhibiting TRPV1 activity, administering a therapeutically effectiveamount of a compound of formula (I) according to claim 1, or apharmaceutically acceptable salt thereof.
 29. The method according toclaim 28, wherein the disorder is selected from the group of pain,neuropathic pain, migraine, ostheoarthritis pain, chronic lower pain,allodynia, pain associated with inflammation, bladder overactivity, andurinary incontinence.